Tetrahydroquinoxalines acting as bradykinin antagonists

ABSTRACT

The invention relates to novel tetrahydroquinoxalines and processes for their preparation, their use for the treatment and/or the prophylaxis of diseases, in particular for the treatment and/or prophylaxis of states of pain.

[0001] The invention relates to novel tetrahydroquinoxalines andprocesses for their preparation, their use for the treatment and/orprophylaxis of diseases, in particular for the treatment and/orprophylaxis of states of pain.

[0002] Kinins are peptides which are produced in the plasma (bradykinin)and peripheral tissue (kallidin) owing to injuries, inflammations,asthma and in anaphylactic and endotoxic shock. In addition to theimportant role played by kinins in cardiovascular homeostasis or thecontraction and relaxation of smooth muscles (Bhoola al. Pharmacol. Rev.1992, 44, 1-80), they result in particular in pain, inflammation andhyperalgesia. Since they in turn promote the production of other painmediators such as prostaglandins, tachykinins and interleukins, there isa further potentiation of the pain response.

[0003] Kinins act via two Gq/11 protein-coupled 7 transmembrane receptorsubtypes; whereas the bradykinin 2 receptor (B2-R) is activated bybradykinin and kallidin, the main fragments thereof, des-Arg9-bradykininand des-Arg10-kallidin, are the preferred agonists for the bradykinin 1receptor (B1-R). Receptor activation leads firstly to stimulation ofphospholipase C and thus to release of intracellular calcium ions,secondly to activation of phospholipase A2 which opens ion channels byprotein kinase C and thus brings about depolarization and excitation ofthe cell (Textbook of Pain, 4th edition; Wall and Melzack, Editors;Edinburgh, 1999, pages 61-62).

[0004] B1-R is, in contrast to B2-R, downregulated under physiologicalconditions, and is expressed and upregulated in cells throughstimulation of disease-related mediators, e.g. interleukins. Ittherefore makes a contribution in particular to the chronic phase of theinflammatory response and to maintaining persistent hyperalgesia. Inaddition, B1-R is involved in central sensitization (Pesquero et al.Proc. Nat. Acad. Sci. USA, 2000, 97, 8140-8145) and in the modulation ofspinal plasticity (Wotherspoon, G. and J. Winter Neurosci. Lett. 2000,294, 175-178).

[0005] It is therefore sensible to use B1-R antagonists for thetreatment of patients with inflammatory pain, neuropathic pain and(lower) back pain, pain associated with osteoarthritis, and painassociated with another etiology.

[0006] B1-R antagonists are also suitable for the treatment of asthma,diabetic vasculopathy, rhinitis, septic shock, atherosclerosis, multiplesclerosis or rheumatoid arthritis.

[0007]2-[3-Oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamideis disclosed in CAPLUS 1973, 136227, without stating a technical effect.

[0008] EP-A-0 509 398 and WO 00/00478 describe tetrahydroquinoxalines asHIV reverse transcriptase inhibitors for the treatment of viraldiseases.

[0009] DE-A43 41 663 discloses tetrahydroquinoxalines as endothelinreceptor antagonists for the treatment of, inter alia, migraine.

[0010] The present invention relates to compounds of the generalformulae (I) and (Ia)

[0011] in which

[0012] A is (C₁-C₆)-alkanediyl,

[0013] E is a bond or (C₁-C₆)-alkanediyl,

[0014] Y is CO or SO₂,

[0015] R¹, R², R³ and R⁴ are identical or different and are hydrogen,halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano,amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino,(C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,carbamoyl or carboxyl,

[0016] R⁵ is (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryland heteroaryl are optionally substituted identically or differently byradicals selected from the group of halogen, trifluoromethyl,trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkylthio, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino,(C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,carbamoyl, carboxyl, phenyl, 5- to 6-membered heteroaryl,propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxapropane-1,3-diyl or1,4-dioxabutane-1,4-diyl,

[0017] in which phenoxy, phenyl and 5- to 6-membered heteroaryl are inturn optionally substituted identically or differently bytrifluoromethyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or halogen,

[0018] R⁶ and R⁷ are identical or different and are hydrogen,(C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl, 3- to 12-memberedcarbocyclyl, 4- to 12-membered heterocyclyl, or

[0019] are (C₁-C₁₀)-alkyl which is optionally substituted by halogen ora radical selected from the group of (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryl, 5-to 10-membered heteroaryl, 3- to 12-membered carbocyclyl and 4- to12-membered heterocyclyl,

[0020] where aryl, heteroaryl, heterocyclyl and carbocyclyl areoptionally substituted identically or differently by radicals selectedfrom the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl,nitro, cyano, amino, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, 5- to 7-memberedheterocyclyl, (C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkylthio, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino,(C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,carbamoyl, carboxyl, phenyl, 5- to 6-membered heteroaryl,propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxapropane-1,3-diyl or1,4-dioxabutane-1,4-diyl,

[0021] or

[0022] R⁶ and R⁷ together with the nitrogen atom form a 4- to12-membered heterocyclyl radical which is bonded via nitrogen and whichis optionally substituted identically or differently by radicalsselected from the group of halogen, trifluoromethyl, trifluoromethoxy,hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₆)-acyloxy, (C₁-C₆)-acyl, (C₁-C₆)-acylamino,(C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,carbamoyl, carboxyl, (C₃-C₈)-cycloalkyl and phenyl,

[0023] where alkyl, cycloalkyl and phenyl in turn are optionallysubstituted identically or differently by one to three radicals selectedfrom the group of halogen, phenyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and(C₁-C₆)-alkylthio, in which phenyl in turn is optionally substitutedidentically or differently by radicals selected from the group ofhalogen or methyl,

[0024] R⁸ is hydrogen or (C₁-C₃)-alkyl which is optionally substitutedby fluorine,

[0025] R⁹ is hydrogen or (C₁-C₆)-alkyl,

[0026] and the salts, hydrates and/or solvates thereof,

[0027] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0028] The compounds of the invention may exist in stereoisomeric formswhich either are related as image and mirror image (enantiomers) orwhich are not related as image and mirror image (diastereomers). Theinvention relates both to the enantiomers or diastereomers or respectivemixtures thereof. These mixtures of enantiomers and diastereomers can beseparated into the stereoisomerically pure constituents in a knownmariner.

[0029] Salts preferred for the purposes of the invention arephysiologically acceptable salts of the compounds of the invention.

[0030] Physiologically acceptable salts of the compounds of theinvention may be acid addition salts of the compounds with mineralacids, carboxylic acids or sulfonic acids. Particularly preferredexamples are salts with hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid,acetic acid, propionic acid, lactic acid, tartaric acid, citric acid,fumaric acid, maleic acid or benzoic acid.

[0031] Salts which may also be mentioned, however, are salts withconventional bases such as, for example, alkali metal salts (e.g. sodiumor potassium salts), alkaline earth metal salts (e.g. calcium ormagnesium salts) or ammonium salts derived from ammonia or organicamines such as, for example, diethylamine, triethylamine,ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,dihydroabietylamine, 1-ephenamine or methylpiperidine.

[0032] Hydrates of the compounds of the invention are stoichiometriccompositions of the compounds or its salts with water.

[0033] Solvates of the compounds of the invention are stoichiometriccompositions of the compounds or its salts with solvent.

[0034] (C₁-C₆)-Acyl represents for the purposes of the invention astraight-chain or branched acyl radical having 1 to 6, preferably 1 to4, carbon atoms. Preferred examples which may be mentioned are: acetyl,ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl,isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. Acetyl andethylcarbonyl are particularly preferred.

[0035] (C₁-C₆)-Acyloxy represents for the purposes of the invention astraight-chain or branched acyl radical having 1 to 6, preferably 1 to4, carbon atoms which is bonded via an oxygen atom. Preferred exampleswhich may be mentioned are: acetyloxy, ethylcarbonyloxy,propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy,isobutylcarbonyloxy, pentylcarbonyloxy and hexylcarbonyloxy. Acetyloxyand ethylcarbonyloxy are particularly preferred.

[0036] (C₁-C₆)-Acylamino represents for the purposes of the invention astraight-chain or branched acyl radical having 1 to 6, preferably 1 to4, carbon atoms which is bonded via a nitrogen atom. Preferred exampleswhich may be mentioned are: acetylamino, ethylcarbonylamino,propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino,isobutylcarbonylamino, pentylcarbonylamino and hexylcarbonylamino.Acetylamino and ethylcarbonylamino are particularly preferred.

[0037] (C₁-C₆)-Alkanediyl represents for the purposes of the invention astraight-chain or branched alkanediyl radical having 1 to 6, preferably1 to 4, carbon atoms. Preferred examples which may be mentioned aremethylene, ethylene, ethane-1,1-diyl, propylene, propane-1,2-diyl,propane-2,2-diyl. Methylene is preferred.

[0038] (C₁-C₆)-Alkoxy represents a straight-chain or branched alkoxyradical having 1 to 6, preferably 1 to 4, carbon atoms. Preferredexamples which may be mentioned are: methoxy, ethoxy, n-propoxy,isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

[0039] (C₁-C₆)-Alkoxycarbonyl represents a straight-chain or branchedalkoxycarbonyl radical having 1 to 6, preferably 1 to 4, carbon atoms.Preferred examples which may be mentioned are: methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl andtert-butoxycarbonyl.

[0040] (C₁-C₁₀)-, (C₁-C₆)- and (C₁-C₃)-Alkyl represent a straight-chainor branched alkyl radical having, respectively, 1 to 10, 1 to 6 and 1 to3 carbon atoms. Preference is given in the case of (C₁-C₁₀)-alkyl to astraight-chain or branched alkyl radical having 1 to 6 carbon atoms, inthe case of (C₁-C₆)-alkyl to a straight-chain or branched alkyl radicalhaving 1 to 4 carbon atoms, and in the case of (C₁-C₃)-alkyl to methyl.Preferred examples which may be mentioned are: methyl, ethyl, n-propyl,isopropyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain orbranched alkyl radical having 1 to 3 carbon atoms is particularlypreferred.

[0041] (C₁-C₆)-Alkylthio represents for the purposes of the invention astraight-chain or branched alkylthio radical having 1 to 6, preferably 1to 4, carbon atoms. Preferred examples which may be mentioned are:methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio,n-pentylthio and n-hexylthio. A straight-chain or branched alkylthioradical having 1 to 3 carbon atoms is particularly preferred.

[0042] Mono-(C₁-C₆)-alkylamino represents for the purposes of theinvention an amino group having a straight-chain or branched alkylsubstituent which has 1 to 6, preferably 1 to 4, carbon atoms. Preferredexamples which may be mentioned are: methylamino, ethylamino,n-propylamino, isopropylamino, cyclopropylamino, t-butylamino,n-pentylamino, cyclopentylamino and n-hexylamino.

[0043] Di-(C₁-C₆)-alkylamino represents for the purposes of theinvention an amino group having two identically or differentstraight-chain or branched alkyl substituents each of which has 1 to 6,preferably 1 to 4, carbon atoms. Preferred examples which may bementioned are: N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-methyl-N-cyclopropylamino, N-isopropyl-N-n-propylamino,N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino andN-n-hexyl-N-methylamino.

[0044] Mono-(C₁-C₆)-alkylaminocarbonyl represents for the purposes ofthe invention an amino group having a straight-chain or branched alkylsubstituent which has 1 to 6, preferably 1 to 4, carbon atoms and isbonded via a carbonyl group. Preferred examples which may be mentionedare: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,isopropylaminocarbonyl, cyclopropylaminocarbonyl, t-butylaminocarbonyl,n-pentylaminocarbonyl, cyclopentylaminocarbonyl andn-hexylaminocarbonyl.

[0045] Di-(C₁-C₆)-alkylaminocarbonyl represents for the purposes of theinvention an amino group having two identical or differentstraight-chain or branched alkyl substituents each of which has 1 to 6,preferably 1 to 4, carbon atoms and which is bonded via a carbonylgroup. Preferred examples which may be mentioned are:N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl,N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl,N-methyl-N-cyclopropylaminocarbonyl,N-isopropyl-N-n-propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl,N-ethyl-N-n-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl.

[0046] (C₁-C₈)-Cycloalkyl represents for the purposes of the invention acycloalkyl group having 3 to 8, preferably 5 to 7, carbon atoms.Preferred examples which may be mentioned are: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

[0047] (C₆-C₁₀)-Aryl represents for the purposes of the invention anaromatic radical having 6 to 10 carbon atoms. Preferred aryl radicalsare phenyl and naphthyl.

[0048] Halogen represents for the purposes of the invention generallyfluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromineare preferred. Fluorine and chlorine are particularly preferred.

[0049] 3- to 12-membered carbocyclyl represents for the purposes of theinvention generally a mono- or polycyclic, carbocyclic radical having 3to 12 ring atoms. 3- to 10-membered, in particular 3- to 8-membered,carbocyclyl are preferred. Mono- or bicyclic carbocyclyl is preferred.Monocyclic carbocyclyl is particularly preferred. The carbocyclylradicals may be saturated or partially unsaturated. Saturatedcarbocyclyl radicals are preferred. Likewise preferred are(C₃-C₁₀)-cycloalkyl, very particularly (C₄-C₇)-cycloalkyl. Preferredexamples which may be mentioned are: cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, norborn-1-yl,norborn-2-yl, norborn-7-yl, norborn-2-en-7-yl, cyclooctyl, cubyl,cyclononyl, cyclodecyl, decalinyl, adamant-1-yl, adamant-2-yl.

[0050] 5- to 10-membered heteroaryl represents for the purposes of theinvention generally an aromatic, mono- or bicyclic radical having 5 to10 ring atoms and up to 5 heteroatoms from the series S, O and/or N. 5-to 6-membered heteroaryl having up to 4 heteroatoms are preferred. Theheteroaryl radical may be bonded via a carbon atom or heteroatom.Preferred examples which may be mentioned are: thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl,indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl,isoquinolinyl.

[0051] 4- to 12-membered and 5- to 7-membered heterocyclyl represent forthe purposes of the invention generally a mono- or polycyclic,heterocyclic radical having, respectively, 4 to 12 and 5 to 7 ring atomsand up to 3, preferably 2, heteroatoms or hetero groups from the seriesN, O, S, SO, SO₂. 5- to 7-membered heterocyclyl is preferred. Mono- orbicyclic heterocyclyl is preferred. Monocyclic heterocyclyl isparticularly preferred. O, N and S are preferred as heteroatoms. Theheterocyclyl radicals may be saturated or partially unsaturated.Saturated heterocyclyl radicals are preferred. The heterocyclyl radicalsmay be bonded via a carbon atom or a heteroatom. 5- to 7-membered,monocyclic saturated heterocyclyl radicals having up to two heteroatomsfrom the series O, N and S are particularly preferred. Preferredexamples which may be mentioned are: tetrahydrofuran-2-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl,perhydroazepinyl.

[0052] If radicals in the compounds of the invention are optionallysubstituted, the radicals may, unless otherwise specified, besubstituted one or more times identically or differently. Substitutionby up to three identical or different substituents is preferred.

[0053] Preference is given to compounds of the general formulae (I) and(Ia)

[0054] in which

[0055] A, E, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ R⁸ and R⁹ have theabovementioned meaning,

[0056] and where R⁶ and R⁷ are not both hydrogen,

[0057] and the salts, hydrates and/or solvates thereof,

[0058] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0059] Particular preference is given to compounds of the generalformulae (I) and (Ia)

[0060] in which

[0061] A is methylene, and

[0062] E, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ have theabovementioned meaning,

[0063] and the salts, hydrates and/or solvates thereof,

[0064] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0065] Particular preference is likewise given to compounds of thegeneral formulae (I) and (Ia),

[0066] in which

[0067] Y is CO and

[0068] E, A, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ have theabovementioned meaning,

[0069] and the salts, hydrates and/or solvates thereof,

[0070] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0071] Particular preference is likewise given to compounds of thegeneral formulae (I) and (Ia)

[0072] in which

[0073] R⁵ is phenyl which is optionally substituted identically ordifferently by one to three radicals selected from the group of methyl,chlorine, trifluoromethyl, trifluoromethoxy,

[0074] E is a bond, and

[0075] A, Y, R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and R⁹ have the abovementionedmeaning,

[0076] and the salts, hydrates and/or solvates thereof,

[0077] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0078] Particular preference is likewise given to compounds of thegeneral formulae (I) and (Ia)

[0079] in which

[0080] A is (C₁-C₆)-alkanediyl,

[0081] E is a bond or (C₁-C₆)-alkanediyl,

[0082] Y is CO,

[0083] R¹, R², R³ and R⁴ are identical or different and are hydrogen,halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano,amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino,(C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,carbamoyl or carboxyl,

[0084] R⁵ is (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryland heteroaryl are optionally substituted identically or differently byradicals selected from the group of halogen, trifluoromethyl,trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkylthio, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino,(C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,carbamoyl, carboxyl, phenyl, 5- to 6-membered heteroaryl,propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxapropane-1,3-diyl or1,4dioxabutane-1,4-diyl,

[0085] in which phenoxy, phenyl and 5- to 6-membered heteroaryl are inturn optionally substituted identically or differently bytrifluoromethyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or halogen,

[0086] R⁶ and R⁷ are identical or different and are hydrogen,(C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl, 3- to 12-memberedcarbocyclyl, 4- to 12-membered heterocyclyl, or

[0087] are (C₁-C₁₀)-alkyl which is optionally substituted by halogen ora radical selected from the group of (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryl, 5-to 10-membered heteroaryl, 3- to 12-membered carbocyclyl and 4- to12-membered heterocyclyl,

[0088] where aryl, heteroaryl, heterocyclyl and carbocyclyl areoptionally substituted identically or differently by radicals selectedfrom the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl,nitro, cyano, amino, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, 5- to 7-memberedheterocyclyl, (C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkylthio, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino,(C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,carbamoyl, carboxyl, phenyl, 5- to 6-membered heteroaryl,propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxapropane-1,3-diyl or1,4-dioxabutane-1,4-diyl,

[0089] or

[0090] R⁶ and R⁷ together with the nitrogen atom form a 4- to12-membered heterocyclyl radical which is bonded via nitrogen and whichis optionally substituted identically or differently by radicalsselected from the group of halogen, trifluoromethyl, trifluoromethoxy,hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, mono- ordi-(C₁-C₆)-alkylamino, (C₁-C₆)-acyloxy, (C₁-C₆)-acyl, (C₁-C₆)-acylamino,(C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl,carbamoyl, carboxyl, (C₃-C₈)-cycloalkyl and phenyl,

[0091] where alkyl, cycloalkyl and phenyl in turn are optionallysubstituted identically or differently by one to three radicals selectedfrom the group of halogen, phenyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and(C₁-C₆)-alkylthio, in which phenyl in turn is optionally substitutedidentically or differently by radicals selected from the group ofhalogen or methyl,

[0092] R⁸ is hydrogen,

[0093] R⁹ is hydrogen,

[0094] and the salts, hydrates and/or solvates thereof,

[0095] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0096] Very particular preference is given to compounds of the generalformulae (I) and (Ia)

[0097] in which

[0098] A is methylene or ethylene,

[0099] E is a bond, methylene or ethylene,

[0100] Y is CO,

[0101] R¹, R², R³ and R⁴ are identical or different and are hydrogen,halogen, methyl, ethyl, methoxy, ethoxy, carbamoyl or carboxyl,

[0102] R⁵ is (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryland heteroaryl are optionally substituted identically or differently byradicals selected from the group of halogen, trifluoromethyl,trifluoromethoxy, methyl, ethyl, isopropyl, methoxy, ethoxy, phenoxy,dimethylamino, (C₁-C₆)-alkoxycarbonyl, carbamoyl, carboxyl, phenyl, 5-to 6-membered heteroaryl and butane-1,4-diyl,

[0103] where phenoxy, phenyl and 5- to 6-membered heteroaryl areoptionally substituted by trifluoromethyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxyor halogen,

[0104] R⁶ and R⁷ are identical or different and and are hydrogen,phenyl, 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl,where R⁶ and R⁷ are not both hydrogen, or

[0105] are (C₁-C₁₀)-alkyl which is optionally substituted by a radicalselected from the group of halogen, (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryl, 5- to10-membered heteroaryl, 3- to 12-membered carbocyclyl and 4- to12-membered heterocyclyl,

[0106] where aryl, heteroaryl, heterocyclyl and carbocyclyl areoptionally substituted identically or differently by radicals selectedfrom the group of halogen, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, 5- to 7-membered heterocyclyl,(C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkoxycarbonyl, carbamoyl, carboxyl,phenyl, 5- to 6-membered heteroaryl and butane-1,4-diyl,

[0107] or

[0108] R⁶ and R⁷ together with the nitrogen atom form a 4- to12-membered heterocyclyl radical which is bonded via nitrogen and whichis optionally substituted identically or differently by one to threeradicals selected from the group of halogen, trifluoromethyl,trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,carbamoyl, carboxyl, (C₃-C₈)-cycloalkyl and phenyl,

[0109] where alkyl, cycloalkyl and phenyl in turn are optionallysubstituted identically or differently by radicals selected from thegroup of halogen, phenyl, (C₁-C₆)-alkyl und (C₁-C₆)-alkoxy,

[0110] R⁸ is hydrogen or (C₁-C₃)-alkyl which is optionally substitutedby fluorine,

[0111] R⁹ is hydrogen or (C₁-C₆)-alkyl,

[0112] and the salts, hydrates and/or solvates thereof,

[0113] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0114] Very particular preference is likewise given to compounds of thegeneral formulae (I) and (Ia)

[0115] in which

[0116] A is methylene or ethylene,

[0117] E is a bond, methylene or ethylene,

[0118] Y is CO,

[0119] R¹, R², R³ and R⁴ are identical or different and are hydrogen,halogen, methyl, ethyl, methoxy, ethoxy, carbamoyl or carboxyl,

[0120] R⁵ is (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryland heteroaryl are optionally substituted identically or differently byradicals selected from the group of halogen, trifluoromethyl,trifluoromethoxy, methyl, ethyl, isopropyl, methoxy, ethoxy, phenoxy,dimethylamino, (C₁-C₆)-alkoxycarbonyl, carbamoyl, carboxyl, phenyl, 5-to 6-membered heteroaryl and butane-1,4-diyl,

[0121] where phenoxy, phenyl and 5- to 6-membered heteroaryl areoptionally substituted by trifluoromethyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxyor halogen,

[0122] R⁶ and R⁷ are identical or different and are hydrogen, phenyl, 3-to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, where R⁶ andR⁷ are not both hydrogen, or

[0123] are (C₁-C₁₀)-alkyl which is optionally substituted by a radicalselected from the group of halogen, (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryl, 5- to10-membered heteroaryl, 3- to 12-membered carbocyclyl and 4- to12-membered heterocyclyl,

[0124] where aryl, heteroaryl, heterocyclyl and carbocyclyl areoptionally substituted identically or differently by radicals selectedfrom the group of halogen, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, 5- to 7-membered heterocyclyl,(C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkoxycarbonyl, carbamoyl, carboxyl,phenyl, 5- to 6-membered heteroaryl and butane-1,4-diyl,

[0125] or

[0126] R⁶ and R⁷ together with the nitrogen atom form a 4- to12-membered heterocyclyl radical which is bonded via nitrogen and whichis optionally substituted identically or differently by one to threeradicals selected from the group halogen, trifluoromethyl,trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl,carbamoyl, carboxyl, (C₃-C₈)-cycloalkyl and phenyl,

[0127] where alkyl, cycloalkyl and phenyl in turn are optionalysubstituted identically or differently by radicals selected from thegroup of halogen, phenyl, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy,

[0128] R⁸ is hydrogen,

[0129] R⁹ is hydrogen,

[0130] and the salts, hydrates and/or solvates thereof,

[0131] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0132] Very particular preference is likewise given to compounds of thegeneral formulae (I) and (Ia)

[0133] in which

[0134] A is methylene,

[0135] E is a bond,

[0136] Y is CO,

[0137] R¹, R² R³ and R⁴ are identical or different and each is hydrogen,methyl or halogen,

[0138] R⁵ is phenyl which is optionally substituted identically ordifferently by one to three radicals selected from the group of methyl,isopropyl, methoxy, ethoxy, halogen, p-chlorophenoxy, trifluoromethyland trifluoromethoxy,

[0139] R⁶ and R⁷ are identical or different and

[0140] are hydrogen, phenyl or 5- to 8-membered carbocyclyl, where R⁶and R⁷ are not both hydrogen,

[0141] or

[0142] are (C₁-C₆)-alkyl which is optionally substituted by a radicalselected from the group of (C₁-C₆)-alkoxy, phenyl, 5- to 8-memberedcarbocyclyl and 5- to 8-membered heterocyclyl,

[0143] where phenyl, heterocyclyl and carbocyclyl are optionallysubstitituted identically or differently by one to three radicalsselected from the group of halogen, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, 5- to 7-membered heterocyclyl,(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl and butane-1,4-diyl, and

[0144] R⁸ is hydrogen,

[0145] R⁹ is hydrogen,

[0146] and the salts, hydrates and/or solvates thereof,

[0147] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0148] Very particular preference is likewise given to compounds of thegeneral formulae (I) and (Ia)

[0149] in which

[0150] A is methylene,

[0151] E is a bond,

[0152] Y is CO,

[0153] R¹, R², R³ and R⁴ are identical or different and are hydrogen orhalogen,

[0154] R⁵ is phenyl which is optionally substituted identically ordifferently by one to three radicals selected from the group of methyl,isopropyl, halogen, trifluoromethyl and trifluoromethoxy,

[0155] R⁶ and R⁷ are identical or different and

[0156] are hydrogen, (C₁-C₆)-alkyl, phenyl or 5- to 8-memberedcarbocyclyl, where R⁶ and R⁷ are not both hydrogen, and wherecarbocyclyl and phenyl is optionally substituted identically ordifferently by radicals selected from the group of halogen,trifluoromethyl, trifluoromethoxy, methyl and methoxy,

[0157] R⁸ is hydrogen,

[0158] R⁹ is hydrogen,

[0159] and the salts, hydrates and/or solvates thereof,

[0160] with the exception of2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.

[0161] The invention further relates to processes for preparing thecompounds of the formulae (I) and (Ia).

[0162] In process

[0163] [A] compounds of the general formula (II) or (IIa)

[0164] in which

[0165] A, E, Y, R¹, R², R³, R⁴, R⁵, R⁸ and R⁹ have the abovementionedmeaning, and

[0166] X¹ is halogen, preferably bromine or chlorine, or hydroxyl,

[0167] are reacted with compounds of the general formula (III)

[0168] or the salts thereof, e.g. hydrochloride or hydrobromide salts,

[0169] in which

[0170] R⁶ and R⁷ have the abovementioned meaning

[0171] in the case where X¹ is halogen,

[0172] in inert solvents, where appropriate in the presence of a base,preferably in a temperature range from 0° C. to 50° C. under atmosphericpressure, to give compounds of the general formula (I) or (Ia).

[0173] Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane, tetrachloromethane, trichloroethane,tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers suchas diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or petroleumfractions, or other solvents such as nitromethane, ethyl acetate,acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane,2-butanone, dimethyl sulfoxide, acetonitrile, pyridine orhexamethylphosphoric triamide, with preference for tetrahydrofuran ormethylene chloride.

[0174] Examples of bases are alkali metal hydroxides such as sodium orpotassium hydroxide, or alkali metal carbonates such as cesiumcarbonate, sodium or potassium carbonate, or amides such as lithiumdiisopropylamide, or other bases such as DBU, triethylamine ordiisopropylethylaamine, preferably triethylamine.

[0175] In the case where X¹ is hydroxyl,

[0176] compounds of the general formula (II) or (IIa)

[0177] are reacted in inert solvents in the presence of conventionalcondensing agents, where appropriate in the presence of a base,preferably in a temperature range from room temperature to 50° C. underatmospheric pressure, to give compounds of the general formula (I) or(Ia).

[0178] Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane, tetrachloromethane, trichloroethane,tetrachloroethane, 1,2 dichloroethane or trichloroethylene, ethers suchas diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or petroleumfractions, or other solvents such as nitromethane, ethyl acetate,acetone, dimethylformamide, dimethylacetamide, 1,2 dimethoxyethane,dimethyl sulfoxide, acetonitrile or pyridine, with preference fortetrahydrofuran, dimethylformamide or methylene chloride.

[0179] Examples of conventional condensing agents are carbodiimides suchas, for example, N,N′-diethyl-, N,N,′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),N-cyclohexylcarbodiimide-N′-propyloxymethyl-polystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic acid, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), orbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(BOP), or mixtures thereof.

[0180] Examples of bases are alkali metal carbonates such as, forexample, sodium or potassium carbonate, or bicarbonate, or organic basessuch as trialkylamines, e.g. triethylamine, N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

[0181] Particular preference is given to the combination ofN-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)and 1-hydroxybenzotriazole (HOBt), and to the combination ofN-cyclohexylcarbodiimide-N′-propyloxymethyl-polystyrene(PS-carbodiimide) and 1-hydroxybenzotriazole (HOBt) and to thecombination of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and diisopropylethylamine.

[0182] The compounds of the general formula (III) are known or can besynthesized from the appropriate precursors by known processes.

[0183] The preparation of the compounds of the general formulae (II) and(IIa) is described hereinafter: (II-1) and (IIa-1) for Y═CO, (II-2) and(IIa-2) for Y═SO₂.

[0184] In process

[0185] [B] compounds of the general formula (Ib)

[0186] in which

[0187] A, E, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ have theabovementioned meaning, are reacted

[0188] with compounds of the general formula (IV),

X²—R¹⁰  (IV)

[0189] in which

[0190] R¹⁰ is (C₁-C₆)-alkyl, and

[0191] X² is halogen, preferably bromine or iodine,

[0192] in inert solvents in the presence of a base, where appropriate inthe presence of potassium iodide, preferably in a temperature range fromroom temperature to the reflux of the solvent under atmosphericpressure, to give compounds of the general formula (I) or (Ia).

[0193] Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane or 1,2-dichloroethane, ethers such asdioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents suchas acetone, dimethylformamide, dimethylacetamide, 2-butanone oracetonitrile, preferably tetrahydrofuran and methylene chloride.

[0194] Examples of bases are alkali metal carbonates such as cesiumcarbonate, sodium or potassium carbonate, or sodium or potassiummethanolate, or sodium or potassium ethanolate or potassiumtert-butoxide, or other bases such as sodium hydride, potassiumhexadimethyldisilazide, lithium hexadimethyldisilazide or DBU,preferably potassium hexadimethyldisilazide or sodium hydride.

[0195] The compounds of the general formula (IV) are known or can besynthesized from the appropriate precursors by known processes.

[0196] In process

[0197] [C] compounds of the general formula (V)

[0198] in which

[0199] A, Y, R¹, R², R³, R⁴, R⁶, R⁷ and R⁸ have the abovementionedmeaning, are reacted

[0200] with compounds of the general formula (VI),

[0201] in which

[0202] E and R⁵ have the abovementioned meaning, and

[0203] X³ is halogen, preferably bromine or chlorine,

[0204] in inert solvents, where appropriate in the presence of a base,preferably in a temperature range from room temperature to the reflux ofthe solvent under atmospheric pressure, to give compounds of the generalformula (Ib).

[0205] Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane or 1,2-dichloroethane, ethers such as diethylether, dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbonssuch as benzene, xylene or toluene, or other solvents such as acetone,dimethylformamide, 2-butanone, acetonitrile or pyridine, with preferencefor pyridine, acetonitrile, methylene chloride or tetrahydrofuran.

[0206] Examples of bases are alkali metal carbonates such as cesiumcarbonate, sodium or potassium carbonate, or sodium or potassiummethanolate, or sodium or potassium triethylamine, diisopropylethylamineor pyridine, with preference for alkali metal carbonates such as cesiumcarbonate, sodium or potassium carbonate or pyridine.

[0207] The compounds of the general formula (VI) are known or can besynthesized from the appropriate precursors by known processes.

[0208] The compounds of the general formula (V) can be prepared from theappropriate precursors in analogy to synthetic processes indicatedhereinafter for the compounds of the general formula (X).

[0209] Compounds of the general formula (Va)

[0210] in which

[0211] R¹, R², R³, R⁴, R⁶ and R⁸ have the abovementioned meaning,

[0212] are prepared by reacting compounds of the general formula (VII)

[0213] in which

[0214] R¹, R², R³ and R⁴ have the abovementioned meaning,

[0215] with compounds of the general formula (VIII)

[0216] in which

[0217] R⁶ and R⁸ have the abovementioned meaning,

[0218] in inert solvents, preferably in a temperature range from roomtemperature to the reflux of the solvent under atmospheric pressure.

[0219] Examples of inert solvents are alcohols such as methanol,ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or mixturesof said solvents, where appropriate with water, with preference for amixture of ethanol and water.

[0220] The compounds of the general formulae (VII) and (VIII) are knownor can be synthesized from the appropriate precursors by known processes(cf. for (VIII): J. Romanenko, et al., Chem. Heterocycl. Compd. (Engl.Trans.) 9, 1973, 244).

[0221] Compounds of the general formula (II-1) or (IIa-1) are preparedby reacting compounds of the general formula (IX) or (IXa)

[0222] in which

[0223] A, E, R¹, R², R³, R⁴, R⁵, R⁸ and R⁹ have the abovementionedmeaning, and

[0224] R¹¹ is (C₁-C₆)-alkyl, preferably methyl and ethyl,

[0225] with bases, in inert solvents, preferably in a temperature rangefrom room temperature to 60° C. under atmospheric pressure.

[0226] Examples of bases are alkali metal hydroxides such as sodium,lithium or potassium hydroxide, or alkali metal carbonates such ascesium carbonate, sodium or potassium carbonate, preferably sodiumhydroxide or lithium hydroxide.

[0227] Examples of inert solvents are halohydrocarbons such as methylenechloride, tetrachloromethane, trichloroethane, tetrachloroethane,1,2-dichloroethane or trichloroethylene, ethers such as diethyl ether,methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols suchas methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, or mixtures of said solvents, where appropriate withwater, preferably tetrahydrofuran and/or methanol or a mixture of waterand ethanol or a mixture of water and dioxane.

[0228] Compounds of the general formula (IX) or (IXa) when R⁹═R¹⁰ areprepared by reacting compounds of the general formula (IXb)

[0229] in which

[0230] A, E, R¹, R², R³, R⁴, R⁵, R⁸ and R¹¹ have the abovementionedmeaning,

[0231] with compounds of the general formula (IV) under the reactionconditions described in process [B].

[0232] Compounds of the general formula (IXb) are prepared by reactingcompounds of the general formula (X)

[0233] in which

[0234] A, R¹, R², R³, R⁴, R⁸ and R¹¹ have the abovementioned meaning,

[0235] with compounds of the general formula (VI) under the reactionconditions described in process [C].

[0236] Compounds of the general formula (X) are prepared by reactingcompounds of the general formula (XI)

[0237] in which

[0238] A, R¹, R², R³, R⁴, R⁸ and R¹¹ have the abovementioned meaning,and

[0239] R¹² is (C₁-C₆)-alkyl, preferably methyl and ethyl,

[0240] under with a reducing agent in inert solvents, preferably in atemperature range from room temperature to the reflux of the solventunder atmospheric pressure up to 3 bar (cf. R. C. Larock, ComprehensiveOrganic Transformations, VCH Verlagsgesellschaft, 1989, pages 411-415).

[0241] Examples of reducing agents are palladium on activated carbon andhydrogen, tin dichloride or titanium trichloride, with preference forpalladium on activated carbon and hydrogen or tin dichloride.

[0242] Examples of inert solvents are ethers such as diethyl ether,methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols suchas methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane,cyclohexane or petroleum fractions, or other solvents such as ethylacetate, dimethylformamide, dimethylacetamide, acetonitrile or pyridine,preferred solvents being methanol, ethanol, isopropanol or, in the caseof tin dichloride, in ethanol, methanol or dimethylformamide.

[0243] Compounds of the general formula (XI) are prepared by reactingcompounds of the general formula (XII)

[0244] in which

[0245] R¹, R², R³ and R⁴ have the abovementioned meaning,

[0246] with compounds of the general formula (XIII),

[0247] in which

[0248] A, R⁸, R¹¹ and R¹² have the abovementioned meaning,

[0249] or the salts thereof, e.g. hydrochloride or hydrobromide salts,

[0250] in inert solvents, where appropriate in the presence of a base,preferably in a temperature range from room temperature to the reflux ofthe solvent under atmospheric pressure.

[0251] Examples of inert solvents are ethers such as1,2-dimethoxyethane, dioxane, glycol dimethyl ether or diethylene glycoldimethyl ether, hydrocarbons such as benzene, xylene, toluene orpetroleum fractions, or other solvents such as dimethylformamide,dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine, withdimethyl sulfoxide being preferred as solvent.

[0252] Examples of bases are alkali metal carbonates such as cesiumcarbonate, sodium or potassium carbonate, or amides such as sodamide,lithium bis(trimethylsilyl)amide, lithium diisopropylamide, ororganometallic compounds such as butyllithium or phenyllithium, or otherbases such as sodium hydride, DBU, triethylamine ordiisopropylethylamine, preferably diisopropylethylamine ortriethylamine.

[0253] The compounds of the general formulae (XII) and (XIII) are knownor can be synthesized from the appropriate precursors by known processes[cf. for (VIII): Drysdale et al. Bioorg. Med. Chem. Lett. 1998, 8,133-138.4; Aitken et al. Synthesis 1997, 787-791; Larsson et al. ActaChem. Scand. 1994, 48, 517-525, Trost et al. J. Org. Chem. 1988, 53,532).

[0254] Compounds of the general formula (II-2) or (IIa-2)

[0255] in which

[0256] A, E, R¹, R², R³, R⁴, R⁵, R⁸ and R⁹ have the abovementionedmeaning, and

[0257] X⁴ is halogen, preferably chlorine,

[0258] are prepared by reacting compounds of the general formula (XIV)or (XIVa),

[0259] in which

[0260] A, E, R¹, R², R³, R⁴, R⁵, R⁸ and R⁹ have the abovementionedmeaning,

[0261] with potassium nitrate and sulfuryl chloride in inert solvents,preferably in a temperature range from room temperature to the reflux ofthe solvent at atmospheric pressure.

[0262] Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane, tetrachloromethane, trichloroethane,tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers suchas 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such asbenzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, orother solvents such as ethyl acetate, dimethylformamide,dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine, withacetonitrile being preferred as solvent.

[0263] The compounds of the general formula (I) of the invention aresuitable for use as medicaments for the treatment and/or prophylaxis ofdiseases in humans and animals.

[0264] The compounds of the invention show a valuable range ofpharmacological effects which could not have been predicted.

[0265] The compounds of the invention have B1 receptor antagonisticeffects.

[0266] The compounds of the invention can, by reason of theirpharmacological properties, be employed alone or in combination withother medicaments for the prophylaxis and treatment of acute and/orchronic pain (for a classification, see “Classification of Chronic Pain,Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms”,2^(nd) Edition., Meskey and Begduk, Editors; IASP-Press, Seattle, 1994),especially for the treatment of cancer-induced pain and chronicneuropathic pain such as, for example, associated with diabeticneuropathy, post-herpetic neuralgia, peripheral nerve damage, centralpain (for example resulting from cerebral ischemia) and trigeminalneuralgia, and other chronic pain such as, for example, lumbago, (low)back pain, inflammatory or rheumatic pain. These substances are moreoversuitable for the therapy of primarily acute pain of any etiology and ofsecondary states of pain resulting therefrom, and for the therapy ofstates of pain which were formerly acute and have become chronic.

[0267] Bradykinin 1 antagonists are furthermore suitable for thetreatment of asthma, diabetic vasculopathy, rhinitis, septic shock,atherosclerosis, multiple sclerosis or rheumatoid arthritis.

[0268] The in vitro effect of the compounds of the invention can beshown using the following biological assays:

[0269] 1. Functional in vitro Assay

[0270] Agonists such as des-Arg9-BK and des-Arg10-kallidin activate theB1 receptor and lead, via stimulation of phospholipase C, to release ofcalcium ions from intracellular stores. Antagonists block the activationof the receptor by the agonists and thus also the agonist-dependentstimulation of phospholipase C and the intracellular calcium releaseinduced thereby.

[0271] A functional in vitro assay can be carried out with stable celllines, e.g. CHO or HEK 293, which recombinantly express the human B1receptor. This entails measuring the activation of the receptor by theagonist indirectly via the intracellular calcium release induced thereby(in microtiter plates with 96, 384 and 1536 wells/plate). The effect ofthe tested substances can be stated as IC₅₀.

[0272] In this assay, Examples 170 and 177 have IC₅₀ values of 25 nM and17 nM, respectively.

[0273] 2. Binding to CHO BK1 Membranes

[0274] The binding of ligands to the B1 receptor from B1-transfected CHOcell membranes is carried out by the method of Levesque et al.(Immunopharmacol. 1995, 29, 141-147). Incubation buffer (Tris-HCl bufferpH 7.4+1 mM phenanthrolines, 0.14 g/l bacitracin), labeled radioligand[³H]-desArg10-kallidin (0.5 nM), DMSO or test stubstance all pipettedtogether, and then 250 μg of protein are added, and the mixture isthoroughly mixed and incubated at RT for 90 min. After expiry of theincubation time, the reaction is stopped by adding ice-cold Tris-HClbuffer to each tube. Filtration through Whatman GF/B filters (in 0.6%polyetylenimines) is followed by washing with 2×3 ml of Tris-HCl buffer.The filters are transferred into minivials, and the radioactivity isdetermined in a liquid scintillation counter. The effect of the testedsubstances can be stated as K_(i) or IC₅₀.

[0275] The suitability of the compounds of the invention for thetreatment of states of pain, especially neuropathic states of pain, canbe shown in the following animal models:

[0276] 3. Model of Acute Inflammatory Pain (Carrageenin Model) in Rats

[0277] This model follows the description by Winter et al. (Proc. Soc.Exp. Biol. Med., 1962, 111, 544-547).

[0278] Rats receive subplantar injections of a suspension of carrageeninin the right rear paw (0.35 mg per paw in 0.10 ml of physiologicalsaline). Two hours later, the rats are thermally stimulated successivelyon the noninflamed and on the inflamed rear paw.

[0279] The thermal stimulation apparatus (Ugo Basile, Ref.: 7371)consists of 6 individual Plexiglas boxes (17×11×13 cm) placed on anelevated glass plate. A rat is is put in the box for 30 min forhabituation. Then a movable infrared source (Setting 20) is focussedunder the noninflamed and the inflamed rear paw, and the latency timesuntil the paw is withdrawn are recorded automatically. The withdrawal ofthe paw interrupts the reflected beam and thus automatically switchesoff the counter and light source. To avoid tissue damage, the test isstopped after 45 s even if no paw-withdrawal response is recorded.

[0280] At least 12 rats are investigated in each group: male Wistar(Han) rats, 180-220 g. The test is carried out blind.

[0281] The data are analyzed by comparing the treated groups with thecorresponding control by means of the unpaired Student's test.

[0282] The novel active ingredients can be converted in a known mannerinto conventional formulations such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable carriers or solvents. Inthese, the therapeutically active compound should be present in eachcase in a concentration of about 0.5 to 90% by weight of the completemixture, i.e. in amounts which are sufficient to achieve the stateddosage range.

[0283] The formulations are produced for example by extending activeingredients with solvents and/or carriers, where appropriate with use ofemulsifiers and/or dispersants, it being possible, for example whenwater is used as diluent, where appropriate to use organic solvents asauxiliary solvents.

[0284] Administration takes place in a conventional way, preferablyorally, transdermally or parenterally, especially perlingually orintravenously. However, it can also take place by inhalation through themouth or nose, for example with the aid of a spray, or topically via theskin.

[0285] It has generally proved advantageous to administer amounts ofabout 0.001 to 25 mg/kg, preferably about 0.1 to 10 mg/kg, of bodyweight, on oral use about 0.01 to 25 mg/kg, preferably about 0.5 to 5mg/kg, of body weight to achieve effective results.

[0286] It may nevertheless be necessary where appropriate to deviatefrom the amounts mentioned, in particular as a function of the bodyweight and the mode of administration, of the individual response to themedicament, of the nature of its formulation and the time or intervalover which administration takes place. Thus, in some cases it maysufficient to make do with less than the aforementioned minimum amount,whereas in other cases the upper limit mentioned must be exceeded. Wherelarger amounts are administered, it may be advisable to distribute thesein a plurality of single doses over the day.

[0287] Abbreviations:

[0288] abs. absolute

[0289] Ac acetyl

[0290] acac acetylacetonyl

[0291] AIBN α, α′-azobis(isobutyronitrile)

[0292] Aloc allyloxycarbonyl

[0293] aq. aqueous

[0294] 9-BBN 9-borabicyclo[3.3.1]nonane

[0295] Bn benzyl

[0296] Boc tert-butoxycarbonyl

[0297] Bom benzyloxymethyl

[0298] BOP benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate

[0299] b.p. boiling point

[0300] Bu butyl

[0301] Bz benzoyl

[0302] CAN cerium ammonium nitrate

[0303] Cbz benzyloxycarbonyl

[0304] CDI N,N′-carbonyldiimidazole

[0305] cf. compare

[0306] CH cyclohexane

[0307] conc. concentrated

[0308] Cp cyclopentadienyl

[0309] cryst. crystalline/crystallized

[0310] CSA 10-camphorsulfonic acid

[0311] Dabco 1,4-diazabicyclo[2.2.2]octane

[0312] DAST diethylaminosulfur trifluoride

[0313] DBN 1,5-diazabicyclo[4.3.0]non-5-ene

[0314] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0315] DCC N,N′-dicyclohexylcarbodiimide

[0316] DCE 1,2-dichloroethane

[0317] DCI direct chemical ionization (in MS)

[0318] DCM dichloromethane

[0319] DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

[0320] DEAD diethyl azodicarboxylate

[0321] d.e. diastereomeric excess

[0322] decomp. decomposition

[0323] DHP 3,4-dihydro-2h-pyran

[0324] DIAD diisopropyl azodicarboxylate

[0325] DIBAH diisobutylaluminum hydride

[0326] DIC diisopropylcarbodiimide

[0327] DIEA N,N-diisopropylethylamine

[0328] dil. dilute

[0329] dist. distilled

[0330] DMA N,N-dimethylacetamide

[0331] DMAP 4-N,N-dimethylaminopyridine

[0332] DME 1,2-dimethoxyethane

[0333] DMF N,N-dimethylformamide

[0334] DMPU N,N′-dimethylpropyleneurea

[0335] DMSO dimethyl sulfoxide

[0336] DNPH 2,4-dinitrophenylhydrazine

[0337] DPPA diphenylphosphoryl azide

[0338] EDC N′-(3-dimethylaminopropyl)-n-ethylcarbodiimide×HCl

[0339] e.e. enantiomeric excess

[0340] EA ethyl acetate (acetic acid ethyl ester)

[0341] EI electron impact ionization (in MS)

[0342] eq equivalent(s)

[0343] ESI electrospray ionization (in MS)

[0344] Et ethyl

[0345] Fmoc fluorenylmethoxycarbonyl

[0346] Fr. fraction

[0347] GC gas chromatography

[0348] HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

[0349] HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

[0350] HMDS 1,1,1,3,3,3-hexamethyldisilazane

[0351] HMPA or HMPT hexamethylphosphoric triamide

[0352] HOBt 1-hydroxy-1H-benzotriazole×H₂O

[0353] HOSu N-hydroxysuccinimide

[0354] HPLC high pressure, high performance liquid chromatography

[0355] Im imidazol-1-yl

[0356] IR infrared spectroscopy

[0357] LAH lithium aluminum hydride

[0358] LC-MS coupled liquid chromatography-mass spectroscopy

[0359] LDA lithium N,N-diisopropylamide

[0360] LiHMDS lithium N,N-bistrimethylsilylamide

[0361] Lit. literature (reference)

[0362] Liq. liquid

[0363] m meta

[0364] mCPBA meta-chloroperbenzoic acid

[0365] Me methyl

[0366] MEK methyl ethyl ketone

[0367] MEM methoxyethoxymethyl

[0368] MOM methoxymethyl

[0369] m.p. melting point

[0370] MPLC medium pressure liquid chromatography

[0371] Ms methanesulfonyl (mesyl)

[0372] MS mass spectroscopy

[0373] MTBE methyl tert-butyl ether

[0374] MW molecular weight

[0375] NBS N-bromosuccinimide

[0376] NCS N-chlorosuccinimide

[0377] NIS N-iodosuccinimide

[0378] NMM N-methylmorpholine

[0379] NMO N-methylmorpholine N-oxide

[0380] NMR nuclear magnetic resonance spectroscopy

[0381] o ortho

[0382] p para

[0383] p.A. analytical grade

[0384] PCC pyridinium chlorochromate

[0385] PDC pyridinium dichromate

[0386] Pfp pentafluorophenyl

[0387] Ph phenyl

[0388] Piv pivaloyl

[0389] PMB p-methoxybenzyl

[0390] PNB p-nitrobenzyl

[0391] PPA polyphosphoric acid

[0392] ppt. precipitate

[0393] PPTS pyridinium p-toluenesulfonate

[0394] Pr propyl

[0395] PS polystyrene (resin)

[0396] py pyridine

[0397] PyBOP benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate

[0398] RF reflux

[0399] R_(f) retention index (in TLC)

[0400] RP reverse phase (in HPLC)

[0401] RT room temperature

[0402] R_(t) retention time (in HPLC)

[0403] sat. saturated

[0404] SEM 2-(trimethylsilyl)ethoxymethyl

[0405] sol. solution

[0406] subl. sublimes

[0407] TBAF tetrabutylammonium fluoride

[0408] TBAI tetrabutylammonium iodide

[0409] TBDMS tert-butyldimethylsilyl

[0410] TBDPS tert-butyldiphenylsilyl

[0411] TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate

[0412] TEA triethylamine

[0413] techn. technical

[0414] Teoc 2-(trimethylsilyl)ethoxycarbonyl

[0415] TES triethylsilyl

[0416] Tf trifluoromethanesulfonyl

[0417] TFA trifluoroacetic acid

[0418] TFAA trifluoroacetic anhydride

[0419] TfOH trifluoromethanesulfonic acid

[0420] THF tetrahydrofuran

[0421] THP tetrahydropyranyl

[0422] TIPS triisopropylsilyl

[0423] titr. titrated

[0424] TLC thin layer chromatography

[0425] TMEDA N,N,N′,N′-tetramethylethylenediamine

[0426] TMOF trimethyl orthoformate

[0427] TMS trimethylsilyl

[0428] TPP triphenylphosphine

[0429] TPPO triphenylphosphine oxide

[0430] Trt trityl

[0431] Ts p-toluenesulfonyl (tosyl)

[0432] TsOH p-toluenesulfonic acid

[0433] v/v volume-to-volume ratio (of a solution)

[0434] Vol. volume

[0435] w/w weight-to-weight ratio (of a solution)

[0436] Z benzyloxycarbonyl

[0437] The LC-MS data were found by the following methods:

[0438] Method A

[0439] HPLC apparatus type: HP 1100

[0440] UV dectector DAD: 208-400 nm

[0441] Column: symmetry C 18; 50 mm×2.1 mm; 3.5 μm

[0442] Ionization: ESI positive/negative

[0443] Oven temperature: 40° C.

[0444] Solvent A: CH₃CN+0.1% formic acid Solvent B: H₂O+0.1% formic acid

[0445] Gradient: Time A:% B:% Flow rate 0.00 10.0 90.0 0.50 4.00 90.010.0 0.50 6.00 90.0 10.0 0.50 6.10 10.0 90.0 1.00 7.50 10.0 90.0 0.50

[0446] Method B

[0447] Column: symmetry C 18; 2.1 mm×150 mm; 5 μm

[0448] Ionization: ESI positive/negative

[0449] Oven temperature: 70° C.

[0450] Solvent B: 0.3 g of HCl (30%)/1 l of water

[0451] Gradient: A/B 2/98 to 95/5 within 2.5 min

[0452] Flow rate: 0.9 ml/min to 1.2 ml/min within 2 min

[0453] Method C

[0454] Instrument: HP 1100 with DAD detection;

[0455] Column: Kromasil RP-18, 60 mm×2 mm, 3.5 μm;

[0456] Eluent: A=5 ml HClO4/l H2O, B=ACN;

[0457] Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B;

[0458] Flow rate: 0.75 ml/min; Temp.: 30° C.; Detection UV 210 nm

[0459] Starting Compounds

EXAMPLE IN-Phenylmethyl-2-(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide

[0460]

[0461] A suspension of 5.00 g (46.2 mmol) of 1,2-phenylenediamine and8.66 g (46.2 mmol) of N-(phenylmethyl)maleimide in 500 ml of 1:1ethanol/water are heated to boiling. After refluxing for 4 hours, themixture is allowed to cool and the resulting precipitate is removed. Thefilter cake is washed with 1:1 ethanol/water and dried in vacuo. 6.64 g(49%) of the target compound are obtained in this way as a yellowishsolid. The filtrate is evaporated and the residue is triturated inisopropanol. A further 1.37 g (10%) are obtained in this way as a paleyellow solid.

[0462]¹H-NMR (200 MHz, DMSO-d₆): δ=2.43 (dd, 1H), 2.71 (m, 1H),4.10-4.16 (m, 1H), 4.16-4.42 (m, 2H), 5.90 (s, br, 1H), 6.54-6.85 (m,4H), 7.17-7.39 (m, 5H), 8.45 (t, 1H), 10.28 (s, br, 1H).

[0463] MS (ESI): m/z=296 [M+H]⁺.

EXAMPLE IIN-(2-Methoxyphenyl)-2-(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide

[0464]

[0465] This compound is obtained in analogy to the method of example Ifrom 1.00 g (9.25 mmol) of 1,2-phenylenediamine and 1.88 g (9.25 mmol)of N-(2-methoxyphenyl)maleimide after refluxing for 3.5 hours andtriturating the resulting precipitate with isopropanol.

[0466] Yield: 1.76 g (61%) as pale yellow solid.

[0467]¹H-NMR (200 MHz, DMSO-d₆): δ=2.52-2.98 (ABX system, AB part, 2H),3.74 (s, 3H), 4.21 (dd, 1H), 6.04 (s, 1H), 6.55-7.10 (m, 7H), 8.06 (d,1H), 9.43 (s, 1H), 10.33 (s, 1H).

[0468] MS (DCI, NH₃): m/z=329 [M+NH₄]⁺, 312 [M+H]⁺.

EXAMPLE III Dimethyl N-(2-nitrophenyl)aspartate

[0469]

[0470] A solution of 53.6 g (380 mmol) of 1-fluoro-2-nitrobenzene, 25.0g (127 mmol) of dimethyl DL-asparatate and 49.1 g (380 mmol) ofN,N-diisopropylethylamine in 150 ml of DMSO is stirred in an argonatmosphere at 60° C. overnight. It is cooled to room temperature, and300 ml each of water and ethyl acetate are added to the mixture. Theaqueous phase is extracted three times with 300 ml of ethyl acetate eachtime, and the combined organic phases are washed twice with 100 ml ofwater each time. The organic phase is dried over sodium sulfate, and thesolvent is distilled off in a rotary evaporator. The crude product ispurified on a flash column (mobile phase: toluene). 21.8 g (61%) of thetarget compound are obtained.

[0471] HPLC: Kromasil C18 60×2 mm; Eluent: water+5‰ HClO₄/acetonitrile,T=30° C., Flow rate=0.75 ml/min, R_(t)=4.3 min.

[0472] MS (DCI, NH₃): m/z=300 [M+NH₄]⁺, 283 [M+H]⁺, 582.4 [2M+NH₄]⁺.

[0473]¹H-NMR (200 MHz, CDCl₃): δ=2.99 (d, 2H), 3.75 (s, 3H), 3.80 (s,3H), 4.70 (m, 1H), 6.76 (dt, 1H), 6.85 (m, 1H), 7.48 (dt, 1H), 8.21 (dd,1H), 8.52 (d, broad, 1H).

EXAMPLE IV Methyl(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetate

[0474]

[0475] A solution of 22.0 g (77.9 mmol) of dimethylN-(2-nitrophenyl)aspartate (example III) and catalytic amounts ofpalladium on activated carbon (10%) in 200 ml of methanol is stirred ina hydrogen atmosphere at room temperature for 48 h. Filtration withsuction through kieselguhr is followed by washing with methanol. Thesolvent is distilled off in a rotary evaporator to result in 16.0 g(93%) of the desired product.

[0476] PLC: Kromasil C18 60×2 mm; Eluent: Water+5% HClO₄/acetonitrile,T=30° C., Flow rate=0.75 ml/min, R_(t)=3.4 min.

[0477] MS (DCI, NH₃): m/z=238.2 [M+NH₄]⁺, 221.2 [M+H]⁺.

[0478]¹H-NMR (200 MHz, CDCl₃): δ=2.72 (dd, 1H), 3.14 (dd, 1H), 3.75 (s,3H), 4.34 (dt, 1H), 4.73 (s, broad, 1H), 6.79-6.82 (m, 3H), 6.91 (m,1H), 8.21 (s, broad, 1H).

EXAMPLE V Methyl2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetate

[0479]

[0480] A solution of 4.00 g (18.2 mmol) of methyl2-(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetate (example IV), 19.9 g(90.8 mmol) of 1,3,5-trimethylbenzenesulfonyl chloride and 12.5 g (90.8mmol) of potassium carbonate in 100 ml of acetonitrile is stirred at 60°C. for 16 h. The solvent is distilled off in a rotary evaporator, andthe residue is taken up in 50 ml of water and extracted three times with100 ml of ethyl acetate each time. The combined organic phases are driedover sodium sulfate, and the solvent is distilled off in a rotaryevaporator. The crude product is purified on a flash column (mobilephase: 9:1 toluene/ethyl acetate) to result in 4.55 g (62%) of the titlecompound.

[0481] HPLC: Kromasil C18 60×2 mm; Eluent: Water+5‰ HClO₄/acetonitrile,T=30° C., Flow rate=0.75 ml/min, R_(t)=4.4 min.

[0482] MS (DCI, NH3): m/z=420.1 [M+NH₄]⁺.

[0483]¹H-NMR (200 MHz, CDCl₃): δ=2.28 (s, 3H), 2.37 (m, 1H), 2.50 (s,6H), 2.55 (m, 1H), 3.60 (s, 3H), 4.94 (dd, 1H), 6.82 (dd, 1H), 6.93 (s,2H), 7.04 (m, 1H), 7.21 (m, 1H), 7.38 (m, 1H), 8.25 (s, broad, 1H).

EXAMPLE VI2-[1-(Mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]aceticacid

[0484]

[0485] 803 mg (33.5 mmol) of lithium hydroxide are added to a solutionof 4.50 g (11.1 mmol) of methyl2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetate(example V) in 160 ml of water/ethanol (1:1) solution, and the mixtureis stirred at RT for 4 h. Most of the ethanol is distilled off in arotary evaporator, and the residue is mixed with 100 ml of ethyl acetateand adjusted to pH 2 with 1 molar aqueous hydrochloric acid. The aqueousphase is extracted six times with 100 ml of ethyl acetate each time. Thecombined organic phases are dried over sodium sulfate, and the solventis distilled off in a rotary evaporator. 3.05 g (70%) of the titlecompound are obtained.

[0486] HPLC: Kromasil C18 60×2 mm; Eluent: Water+5‰ HClO₄/acetonitrile,T=30° C., Flow rate=0.75 ml/min, R_(t)=4.0 min.

[0487] MS (ESI): m/z=389.2 [M+H]⁺.

[0488]¹H-NMR (200 MHz, DMSO-d₆): δ=2.11 (dd, 1H), 2.27 (s, 3H), 2.38 (s,6H), 2.41 (m, 1H), 4.68 (dd, 1H), 6.94 (dd, 1H), 7.00 (m, 1H), 7.05 (s,2H), 7.07 (m, 1H), (dt, 1H).

EXAMPLE VII 1-Cycloheptyl-1H-pyrrole-2,5-dione

[0489]

[0490] 10 g (102 mmol) of maleic anhydride are dissolved in 600 ml oftoluene at room temperature and then 11.54 g (102 mmol) ofcycloheptylamine dissolved in 100 ml of toluene are slowly added. Thereaction solution is then stirred at room temperature for one hour.22.97 g (102 mmol) of zinc bromide are then added to the reactionsolution heated to 80° C., and 32.27 ml (153 mmol) ofhexamethyldisilazane (in 100 ml of toluene) are added dropwise over thecourse of 30 min. The solution is subsequently heated to 100° C. andstirred overnight. After the reaction solution has cooled, the solutionis added to 200 ml of 0.5N HCl, and the organic phase is separated. Theaqueous phase is extracted three times more with 200 ml of ethylacetate, the combined organic phases are dried over magnesium sulfate,and the solvent is distilled off in a rotary evaporator. The crudeproduct is purified on a flash column (mobile phase: cyclohexane/ethylacetate). 18.78 g (94%) of the title compound are obtained as a whitesolid.

[0491]¹H-NMR (200 MHz, DMSO-d₆): δ=1.28-1.81 (m, 10H), 1.88-2.01 (m,2H), 3.84-4.03 (m, 1H), 6.96 (s, 2H).

[0492] LC-MS: R_(t)=9.20;

[0493] MS (EI): m/z=193 [M⁺].

EXAMPLE VIIIN-Cycloheptyl-2-(oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetic acid

[0494]

[0495] A suspension of 6.72 g (62.1 mmol) of 1,2-phenylenediamine and 12g (62.1 mmol) of 1-cycloheptyl-1H-pyrrole-2,5-dione in 200 ml of 1:1ethanol/water are heated to boiling. After refluxing for 12 hours, themixture is allowed to cool, and the resulting precipitate is removed.The filter cake is washed with 1:1 ethanol/water and dried in vacuo.

[0496] 16 g (85%) of the target compound are obtained in this way as ayellowish solid.

[0497]¹H-NMR (300 MHz, DMSO-d₆): δ=1.27-1.88 (m, 12H), 2.31 (dd, 1H),2.59 (dd, 1H), 3.68-3.82 (m, 1H), 4.01-4.11 (m, 1H), 5.79 (s, br, 1H),6.55-6.68 (m, 1H), 6.69-6.78 (m, 3H), 7.82 (d, 1H), 10.22 (s, br, 1H).

[0498] MS (ESI): m/z=302 [M+H]⁺.

[0499] Exemplary Embodiments

EXAMPLE 1N-Cycloheptyl-2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]-acetamnide

[0500]

[0501] A solution of 1.00 g (2.57 mmol) of2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]aceticacid (example VI), 291 mg (2.57 mmol) of cycloheptylamine, 383 mg (2.83mmol) of 1-hydroxy-1H-benzotriazole, 567 mg (2.96 mmol) of EDC and 521mg (5.15 mmol) of triethylamine in 10 ml of DMF is stirred at roomtemperature overnight. The mixture is taken up in 100 ml of ethylacetate and washed three times with 30 ml of water each time. Theorganic phase is washed twice with saturated sodium chloride solutionand dried over sodium sulfate, and the solvent is distilled off in arotary evaporator. The crude product is purified on a flash column(mobile phase: 100:2 dichloromethane/methanol). 550 mg (44%) of thetitle compound are obtained.

[0502] HPLC: Kromasil C18 60×2 mm; Eluent: Water+5‰ HClO₄/acetonitrile,T=30° C., Flow rate=0.75 ml/min, R_(t)=4.7 min.

[0503] MS (DCI, NH3): m/z=484.2 [M+H]⁺.

[0504]¹H-NMR (300 MHz, CDCl₃): δ=1.34-1.69 (m, 10H), 1.89 (m, 2H), 2.25(s, 3H), 2.32 (dd, 1H), 2.41 (s, 6H), 2.50 (dd, 1H), 3.89 (m, 1H), 4.95(dd, 1H), 5.92 (d, broad, 1H), 6.78 (dd, 1H), 6.90 (s, 2H), 7.05 (dt,1H), 7.22 (dt, 1H), 7.41 (d, 1H), 7.59 (s, broad, 1H).

[0505] General Method for Preparing2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetamidesStarting from Aliphatic Amines and the Compound of Example VI:

[0506] A solution of 0.07 mmol of the aliphatic primary or secondaryamine, 40.4 mg (0.10 mmol) of2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]aceticacid (example VI), 15.8 mg (0.121 mmol) of 1-hydroxy-1H-benzotriazoleand 200 mg of PS-carbodiimide (loading 0.94 mmol/g; from Argonaut) in 3ml of dichloromethane is shaken at room temperature overnight. 200 mg ofPS-trisamine (loading 3.85 mmol/g; from Argonaut) are added, and themixture is shaken at room temperature for 6 hours. It is filteredthrough a silica gel cartridge (3 g) and washed with a 95:5dichloromethane/methanol mixture. The mother liquor is mixed with 0.5 mlof a sat. sodium bicarbonate solution and shaken at RT for 30 min. It isfiltered through an Extrelut/silica gel cartridge (1 g of each), and thesolvent is distilled off in vacuo. The respective products are obtainedand analyzed by LC/MS (Eluent:solution A=acetonitrile, solutionB=water+0.6 g of HCl (30%)/l of water, Gradient: A/B 10:90 to A/B 90:10within 4 min; Flow rate 0.6 ml/min; T=50° C.; Column: Kromasil RP-18,2.1×150 mm).

[0507] Examples 2-106 listed in table 1 and 2 are obtained in accordancewith this method. The optically active compounds in table 2 are preparedstarting from dimethyl L-aspartate: TABLE 1 Ex. LC/MS No. StructureYield LC-MS method 2

99% Rt = 4.48 min; MS (ESIpos): 484 [M+H]+ A 3

70% Rt = 4.49 min; MS (ESIpos): 538 [M+H]+ A 4

99% Rt = 4.25 min; MS (ESIpos): 470 [M+H]+ A 5

76% Rt = 4.53 min; MS (ESIpos): 496 [M+H]+ A 6

75% Rt = 4.21 min; MS (ESIpos): 458 [M+H]+ A 7

65% Rt = 4.49 min; MS (ESIpos): 484 [M+H]+ A 8

99% Rt = 4.48 min; MS (ESIpos): 484 [M+H]+ A 9

88% Rt = 4.37 min; MS (ESIpos): 506 [M+H]+ A 10

86% Rt = 4.37 min; MS (ESIpos): 506 [M+H]+ A 11

91% Rt = 4.22 min; MS (ESIpos): 492 [M+H]+ A 12

84% Rt = 4.08 min; MS (ESIpos): 508 [M+H]+ A 13

97% Rt = 3.67 min; MS (ESIpos): 472 [M+H]+ A 14

88% Rt = 4.17 min; MS (ESIpos): 496 [M+H]+ A 15

70% Rt = 4.34 min; MS (ESIpos): 513 [M+H]+ A 16

87% Rt = 4.41 min; MS (ESIpos): 506 [M+H]+ A 17

94% Rt = 4.25 min; MS (ESIpos): 514 [M+H]+ A 18

88% Rt = 4.07 min; MS (ESIpos): 456 [M+H]+ A 19

97% Rt = 4.34 min; MS (ESIpos): 492 [M+H]+ A 20

85% Rt = 4.18 min; MS (ESIpos): 496 [M+H]+ A 21

88% Rt = 4.03 min; MS (ESIpos): 536 [M+H]+ A 22

99% Rt = 4.17 min; MS (ESIpos): 496 [M+H]+ A 23

99% Rt = 4.35 min; MS (ESIpos): 513 [M+H]+ A 24

99% Rt = 4.09 min; MS (ESIpos): 482 [M+H]+ A 25

96% Rt = 4.57 min; MS (ESIpos): 547 [M+H]+ A 26

91% Rt = 4.06 min; MS (ESIpos): 484 [M+H]+ A 27

59% Rt = 3.84 min; MS (ESIpos): 430 [M+H]+ A 28

84% Rt = 3.93 min; MS (ESIpos): 442 [M+H]+ A 29

76% Rt = 3.93 min; MS (ESIpos): 468 [M+H]+ A 30

71% Rt = 3.82 min; MS (ESIpos): 430 [M+H]+ A 31

99% Rt = 4.05 min; MS (ESIpos): 444 [M+H]+ A 32

66% Rt = 2.91 min; MS (ESIpos): 539 [M+H]+ A 33

85% Rt = 4.37 min; MS (ESIpos): 513 [M+H]+ A 34

99% Rt = 4.03 min; MS (ESIpos): 522 [M+H]+ A 35

91% Rt = 4.31 min; MS (ESIpos): 492 [M+H]+ A 36

85% Rt = 4.48 min; MS (ESIpos): 546 [M+H]+ A 37

99% Rt = 4.55 min; MS (ESIpos): 562 [M+H]+ A 38

84% Rt = 3.79 min; MS (ESIpos): 474 [M+H]+ A 39

99% Rt = 4.00 min; MS (ESIpos): 474 [M+H]+ A 40

86% Rt = 3.89 min; MS (ESIpos): 442 [M+H]+ A 41

99% Rt = 3.76 min; MS (ESIpos): 442 [M+H]+ A 42

85% Rt = 3.66 min; MS (ESIpos): 428 [M+H]+ A 43

74% Rt = 4.51 min; MS (ESIpos): 502 [M+H]+ A 44

73% Rt = 4.26 min; MS (ESIpos): 476 [M+H]+ A 45

86% Rt = 2.82 min; MS (ESIpos): 502 [M+H]+ B 46

40% Rt = 2.72 min; MS (ESIpos): 488 [M+H]+ B 47

92% Rt = 2.83 min; MS (ESIpos): 502 [M+H]+ B 48

88% Rt = 2.78 min; MS (ESIpos): 502 [M+H]+ B 49

85% Rt = 2.79 min; MS (ESIpos): 492 [M+H]+ B 50

86% Rt = 2.87 min; MS (ESIpos): 518 [M+H]+ B 51

85% Rt = 2.83 min; MS (ESIpos): 504 [M+H]+ B 52

90% Rt = 2.88 min; MS (ESIpos): 518 [M+H]+ B

[0508] TABLE 2 MS Rt LC/MS Ex. No. Structure [M+H] [min] Yield method 53

464 4.6 75% A 54

458 4 82% A 55

444 4.4 quantitative A 56

459 4.16 quantitative A 57

546 4.46 92% A 58

560 4.49 93% A 59

522 4.07 quantitative A 60

508 4.09 quantitative A 61

479 2.97 quantitative A 62

479 2.66 84% A 63

446 3.47 quantitative A 64

510 4.23 82% A 65

492 4.21 quantitative A 66

614 4.68 quantitative A 67

546 4.36 quantitative A 68

510 4.17 89% A 69

520 4.47 quantitative A 70

501 2.67 quantitative A 71

499 2.76 64% A 72

456 3.98 99% A 73

471 2.63 60% A 74

456 3.91 27% A 75

558 4.59 71% A 76

568 4.81 73% A 77

602 4.96 86% A 78

547 4.62 99% A 79

569 4.46 88% A 80

551 4.31 78% A 81

563 4.15 78% A 82

579 4.57 75% A 83

561 4.39 90% A 84

547 4.27 79% A 85

458 4.15 24% A 86

566 4.02 71% A 87

528 4 65% A 88

484 4.1 37% A 89

493 2.91 96% A 90

493 2.8 70% A 91

560 4.76 84% A 92

522 4.18 96% A 93

482 4.02 71% A 94

515 2.71 78% A 95

547 2.93 69% A 96

486 3.87 69% A 97

440 3.67 70% A 98

460 3.67 44% A 99

499 3.32 44% A 100

470 4.2 46% A 101

507 2.9 98% A 102

561 4.82 82% A 103

567 4.59 62% A 104

563 4.25 67% A 105

601 4.92 75% A 106

581 3.12 99% A

[0509] General Method for Preparing2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetamidesStarting from Aromatic Amines and the Compound of Example VI:

[0510] A solution of 0.08 mmol of the aromatic primary or secondaryamine, 25.3 mg (0.07 mmol) of2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]aceticacid (example VI), 29.7 mg (0.08 mmol) of[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium]hexafluorophosphate(HATU) and 16.8 mg (0.13 mmol) of N,N-diisopropylethylamine in 3 ml ofDMF is shaken at room temperature overnight. It is filtered and thesolvent is distilled off. The residue is filtered through a silica gelcartridge and washed with a 90:10 dichloromethane/methanol solventmixture. It is evaporated and the crude product is purified by apreparative RP-HPLC (Kromasil 100 C18, 5 μm; 50×20 mm; Gradient:acetonitrile/water 15:85 to 90:10, room temperature).

[0511] Examples 107-131 listed in table 3 are obtained in accordancewith this method: TABLE 3 LC/MS Example Structure Yield LC-MS method 107

31% Rt = 4.41 min; MS (ESIpos): 538 [M + H]+ A 108

20% Rt = 4.58 min; MS (ESIpos): 518 [M + H]+ A 109

40% Rt = 4.41 min; MS (ESIpos): 492 [M + H]+ A 110

34% Rt = 4.24 min; MS (ESIpos): 478 [M + H]+ A 111

36% Rt = 4.16 min; MS (ESIpos): 524 [M + H]+ A 112

 5% Rt = 4.71 min; MS (ESIpos): 533 [M + H]+ A 113

46% Rt = 4.51 min; MS (ESIpos): 492 [M + H]+ A 114

34% Rt = 5.23 min; MS (ESIpos): 560 [M + H]+ A 115

 7% Rt = 4.19 min; MS (ESIpos): 522 [M + H]+ A 116

58% Rt = 4.74 min; MS (ESIpos): 506 [M + H]+ A 117

14% Rt = 4.63 min; MS (ESIpos): 532 [M + H]+ A 118

 6% Rt = 4.55 min; MS (ESIpos): 492 [M + H]+ A 119

14% Rt = 4.69 min; MS (ESIpos): 533 [M + H]+ A 120

68% Rt = 4.71 min; MS (ESIpos): 556 [M + H]+ A 121

63% Rt = 4.21 min; MS (ESIpos): 494 [M + H]+ A 122

69% Rt = 4.76 min; MS (ESIpos): 556 [M + H]+ A 123

21% Rt = 4.67 min; MS (ESIpos): 548 [M + H]+ A 124

10% Rt = 4.40 min; MS (ESIpos): 536 [M + H]+ A 125

31% Rt = 4.53 min; MS (ESIpos): 499 [M + H]+ A 126

25% Rt = 4.77 min; MS (ESIpos): 533 [M + H]+ A 127

11% Rt = 4.91 min; MS (ESIpos): 533 [M + H]+ A 128

43% Rt = 2.73 min; MS (ESIpos): 514 [M + H]+ B 129

87% Rt = 2.D2978 min; MS (ESIpos): 510 [M + H]+ B 130

68% Rt = 2.80 min; MS (ESIpos): 534 [M + H]+ B 131

29% Rt = 2.65 min; MS (ESIpos): 530 [M + H]+ B

[0512] General Method for the Sulfonylation ofN-benzyl-2-(3-oxo-1,2,3,4-tetrehydro-2-quinoxalinyl)acetamide (ExampleI):

[0513] A solution of 30.7 mg (0.10 mmol) ofN-benzyl-2-(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide (exampleI) and 0.21 inmol of the sulfonyl chloride in 3 ml of pyridine isstirred at 80° C. in an argon atmosphere overnight. The solvent isdistilled off in vacuo, and the residue is purified by a preparativeRP-HPLC (Kromasil 100 C18, 5 μm; 50×20 mm; Gradient: acetonitrile/water15:85 to 90:10, room temperature).

[0514] Examples 132-159 listed in table 4 are obtained in accordancewith this method: TABLE 4 LC/MS Example Structure Yield LC-MS method 132

 9% Rt = 4.54 min; MS (ESIpos): 597 [M + H]+ A 133

 3% Rt = 4.14 min; MS (ESIpos): 518 [M + H]+ A 134

11% Rt = 3.90 min; MS (ESIpos): 464 [M + H]+ A 135

 2% Rt = 4.15 min; MS (ESIpos): 519 [M + H]+ A 136

 3% Rt = 4.05 min; MS (ESIpos): 500 [M + H]+ A 137

23% Rt = 3.91 min; MS (ESIpos): 486 [M + H]+ A 138

 5% Rt = 3.74 min; MS (ESIpos): 450 [M + H]+ A 139

 2% Rt = 4.11 min; MS (ESIpos): 490 [M + H]+ A 140

19% Rt = 4.24 min; MS (ESIpos): 492 [M + H]+ A 141

14% Rt = 3.96 min; MS (ESIpos): 488 [M + H]+ A 142

 6% Rt = 3.66 min; MS (ESIpos): 466 [M + H]+ A 143

 9% Rt = 3.02 min; MS (ESIpos): 440 [M + H]+ A 144

10% Rt = 3.75 min; MS (ESIpos): 450 [M + H]+ A 145

14% Rt = 3.62 min; MS (ESIpos): 472 [M + H]+ A 146

 2% Rt = 3.87 min; MS (ESIpos): 476 [M + H]+ A 147

14% Rt = 3.87 min; MS (ESIpos): 470 [M + H]+ A 148

43% Rt = 3.59 min; MS (ESIpos): 436 [M + H]+ A 149

 4% Rt = 3.60 min; MS (ESIpos): 454 [M + H]+ A 150

 3% Rt = 3.64 min; MS (ESIpos): 455 [M + H]+ A 151

27% Rt = 3.77 min; MS (ESIpos): 509 [M + H]+ A 152

21% Rt = 3.74 min; MS (ESIpos): 450 [M + H]+ A 153

31% Rt = 3.57 min; MS (ESIpos): 517 [M + H]+ A 154

42% Rt = 2.71 min; MS (ESIpos): 506 [M + H]+ B 155

12% Rt = 4.4 min; MS (ESIpos): 566 [M + H]+ A 156

 7% Rt = 4.01 min; MS (ESIpos): 518 [M + H]+ A 157

56% Rt = 3.9 min; MS (ESIpos): 524 [M + H]+ A 158

 7% Rt = 4.13 min; MS (ESIpos): 532 [M + H]+ A 159

 5% Rt = 4.38 min; MS (ESIpos): 514 [M + H]+ A

[0515] General Method for the Sulfonylation ofN-cycloheptyl-2-(oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide(example VIII):

[0516] A solution of 100 mg (0.33 mmol) ofN-cycloheptyl-2-(oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide and 0.4mmol of the sulfonyl chloride in 59 μl of pyridine and 3 ml ofacetonitrile is stirred at 60° C. in an argon atmosphere overnight. Thesolvent is distilled off in vacuo, and the residue is purified by apreparative RP-HPLC (Kromasil 100 C18, 5 μm; 50×20 mm; Gradient:acetonitrile/water 15:85 to 90:10, room temperature).

[0517] Examples 160-180 listed in table 5 are obtained in accordancewith this method: TABLE 5 LC/MS Example Structure Yield LC-MS method 160

38% Rt = 2.92 min; MS (ESIpos): 512 [M + H]+ B 161

47% Rt = 2.56 min; MS (ESIpos): 506 [M + H]+ B 162

31% Rt = 2.62 min; MS (ESIpos): 506 [M + H]+ B 163

59% Rt = 2.69 min; MS (ESIpos): 470 [M + H]+ B 164

48% Rt = 2.67 min; MS (ESIpos): 550 [M + H]+ B 165

24% Rt = 2.60 min; MS (ESIpos): 520 [M + H]+ B 166

37% Rt = 2.83 min; MS (ESIpos): 504 [M + H]+ B 167

50% Rt = 2.53 min; MS (ESIpos): 472 [M + H]+ B 168

34% Rt = 2.72 min; MS (ESIpos): 534 [M + H]+ B 169

 6% Rt = 2.79 min; MS (ESIpos): 604 [M + H]+ B 170

12% Rt = 4.9 min; MS (ESIpos): 603 [M + H]+ A 171

 9% Rt = 4.D185 min; MS (ESIpos): 525 [M + H]+ A 172

14% Rt = 4.6 min; MS (ESIpos): 579 [M + H]+ A 173

17% Rt = 4.5 min; MS (ESIpos): 545 [M + H]+ A 174

15% Rt = 4.2 min; MS (ESIpos): 511 [M + H]+ A 175

 9% Rt = 3.8 min; MS (ESIpos): 467 [M + H]+ A 176

12% Rt = 4.5 min; MS (ESIpos): 524 [M + H]+ A 177

 6% Rt = 4.3 min; MS (ESIpos): 511 [M + H]+ A 178

17% Rt = 4.6 min; MS (ESIpos): 545 [M + H]+ A 179

13% Rt = 4.7 min; MS (ESIpos): 578 [M + H]+ A 180

26% Rt = 2.78 min; MS (ESIpos): 524 [M + H]+ B

BEISPIEL 181N-Phenylmethyl-2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetamide

[0518]

[0519] 1.02 g (3.44 mmol) ofN-phenylmethyl-2-(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide(example I) are suspended in about 10 ml of acetonitrile, and 3.80 g(17.4 mmol) of 2,4,6-trimethylphenylsulfonyl chloride and 523 mg (3.78mmol) of potassium carbonate are added. The mixture is heated to refluxunder an argon atmosphere for 3 hours. The mixture is then allowed tocool, and the contents of the flask are poured into water. The resultingbrown solid is removed and triturated with diethyl ether. The beigecrude product is purified fuirther by chromatography on silica gel(mobile phase: 1:1 dichloromethane/diethyl ether). This results in 770mg (47%) of the target compound as a pale yellowish solid.

[0520]¹H-NMR (200 MHz, DMSO-d₆): δ=2.07-2.41 (m, 11H), 4.01-4.35 (ABXsystem, AB part, 2H), 4.81 (dd, 1H), 6.89-7.39 (m, 11H), 8.35 (t, 1H),10.65 (s, 1H).

[0521] MS (DCI, NH₃): m/z=495 [M+NH₄]⁺, 478 [M+H]⁺.

EXAMPLE 182N-(2-Methoxyphenyl)-2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetamide

[0522]

[0523] This compound is obtained in analogy to the method of example 86from 642 mg (2.06 mmol) ofN-(2-methoxyphenyl)-2-(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide(example II) and 2.25 g (10.3 mmol) of 2,4,6-trimethylphenylsulfonylchloride by heating to reflux for 2 hours and stirring the initiallyobtained brownish red solid with acetone.

[0524] Yield: 804 mg (79%) of a colorless solid.

[0525]¹H-NMR (200 MHz, DMSO-d₆): δ=2.25 (s, 3H), 2.32 (s, 6H), 2.56 (d,2H), 3.76 (s, 3H), 4.82 (t, 1H), 6.70-7.38 (m, 9H), 7.91 (d, 1H), 9.13(s, 1H), 10.67 (s, 1H).

[0526] MS (DCI, NH₃): m/z=511 [M+NH₄]⁺, 494 [M+H]⁺.

EXAMPLE 183 AND EXAMPLE 1842S-N-Cycloheptyl-2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetamideand2R-N-cycloheptyl-2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetamide

[0527]

[0528] 4 g ofN-cycloheptyl-2RS-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetamide(example 1) are separated into the enantiomers by means of a chiralHPLC.

[0529] Description of method: Sample preparation: 4 g dissolved in 750ml of ethyl acetate Sample loading: 400 mg every 36 min Flow rate: 40ml/min Wave length: 254 nM Solvent: ethyl acetate Packing material: 6784(600*30); LNW 2951; N-MA-L-leu-2,4- dimethylpentyl-amide

[0530] The following are obtained:

[0531]S-N-Cycloheptyl-2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetamide:1.95 g (R_(t)=20.292 min).

[0532] Specific rotation [α]²⁰ _(D)=−88.6° (c=0.485; MeOH).

[0533] andR-N-cycloheptyl-2-[1-(mesitylsulfonyl)-3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl]acetamide:1.75 g (R_(t)=32.925 min).

[0534] Specific rotation [α]²⁰ _(D)=+95.8° (c=0.514; MeOH).

[0535] (The concentration c stated in connection with the specificrotation is defined as the amount of substance (in g) per 100 ml ofsolution. Path length: 100 mm). TABLE 6 MW Yield LC/MS Example Structure[g/mol] % LC-MS/MS method 185

570.85 51 MS(ESIpos): m/z = 570 (M + H) Rt = 2.84 min B 186

570.85 42 MS(ESIpos): m/z = 570 (M + H) Rt = 2.89 min B 187

554.40 66 MS(ESIpos): m/z = 554 (M + H) Rt = 2.78 min B 188

554.40 16 MS(ESIpos): m/z = 554 (M + H) Rt = 2.83 min B 189

550.44 37 MS(ESIpos): m/z = 550 (M + H) Rt = 2.91 min B 190

566.89 44 MS(ESIpos): m/z = 566 (M + H) Rt = 3.02 min B 191

566.89 12 MS(ESIpos): m/z = 566 (M + H) Rt = 3.07 min B 192

566.43 60 MS(DCI): m/z = 583 (M + NH4) 193

495.57 42 MS(ESIpos): m/z = 496 (M + H) Rt = 2.71 min B 194

513.56 44 MS(ESIpos): m/z = 514 (M + H) Rt = 2.72 min B 195

507.61 38 MS(ESIpos): m/z = 508 (M + H) Rt = 2.63 min B 196

499.59 31 MS(ESIpos): m/z = 500 (M + H) Rt = 4.30 min A 197

507.61 18 MS(ESIpos): m/z = 508 (M + H) Rt = 4.47 min A 198

536.41 13 MS(ESIpos): m/z = 536 (M + H) Rt = 4.52 min A 199

512.03 29 MS(ESIpos): m/z = 512 (M + H) Rt = 2.84 min B 200

511.57 34 MS(ESIpos): m/z = 512 (M + H) Rt = 2.75 min B 201

491.61 26 MS(ESIpos): m/z = 492 (M + H) Rt = 2.72 min B 202

512.03 27 MS(ESIpos): m/z = 512 (M + H) Rt = 2.77 min B 203

522.38 20 MS(ESIpos): m/z = 522 (M + H) Rt = 4.34 min A 204

521.63 20 MS(ESIpos): m/z = 522 (M + H) Rt = 2.85 min B 205

505.64 24 MS(ESIpos): m/z = 506 (M + H) Rt = 4.59 min A 206

556.48 25 MS(ESIpos): m/z = 556 (M + H) Rt = 2.82 min B 207

569.68 6 MS(ESIpos): m/z = 570 (M + H) Rt = 2.91 min B 208

574.82 31 MS(DCI): m/z = 593 (M + NH4) 209

576.50 4 MS(ESIpos): m/z = 576 (M + H) Rt = 2.86 min B 210

506.56 68 MS(ESIpos): m/z = 507 (M + H) Rt = 4.43 min A 211

515.99 2 MS(ESIpos): m/z = 516 (M + H) Rt = 4.54 min A 212

536.41 7 MS(ESIpos): m/z = 536 (M + H) Rt = 4.43 min A 213

561.58 28 MS(ESIpos): m/z = 562 (M + H) Rt = 4.70 min A 214

545.58 53 MS(ESIpos): m/z = 546 (M + H) Rt = 4.63 min A 215

545.58 12 MS(ESIpos): m/z = 546 (M + H) Rt = 4.66 min A 216

532.45 22 MS(ESIneg): m/z = 530 (M − H) Rt = 4.71 min A 217

498.00 45 MS(ESIpos): m/z = 498 (M + H) 218

512.03 71 MS(ESIneg): m/z = 510 (M − H) Rt = 4.57 min A 219

542.05 89 MS(ESIpos): m/z = 542 (M + H) Rt = 4.74 min A 220

515.99 37 MS(ESIpos): m/z = 516 (M + H) Rt = 4.44 min A 221

531.99 50 MS(ESIneg): m/z = 530 (M − H) Rt = 4.56 min A 222

532.45 8 MS(ESIpos): m/z = 532 (M + H) Rt = 4.72 min A 223

515.99 29 MS(ESIpos): m/z = 516 (M + H) Rt = 4.53 min A 224

536.41 22 MS(ESIpos): m/z = 536 (M + H) Rt = 4.58 min A 225

560.07 76 MS(ESIpos): m/z = 560 (M + H) Rt = 4.91 min A 226

607.73 7 MS(ESIpos): m/z = 606 (M + H) Rt = 5.00 min A 227

535.52 42 MS(ESIpos): m/z = 536 (M + H) 228

571.93 36 MS(DCI): m/z = 589 (M + NH4) 229

607.73 4 MS(ESIpos): m/z = 605 (M + H) 230

501.96 66 MS(ESIpos): m/z = 502 (M + H) 231

536.41 46 MS(ESIpos): m/z = 536 (M + H) 232

535.52 28 MS(ESIpos): m/z = 536 (M + H) 233

522.38 82 MS(ESIpos): m/z = 522 (M + H) 234

501.96 36 MS(ESIpos): m/z = 502 (M + H) 235

590.38 63 MS(ESIpos): m/z = 590 (M + H) 236

519.61 42.85 LCMS: Rt =2.87 min MS(ESIpos): m/z = 520 (M + H) B 237

463.56 47.4 LCMS: Rt =3.92 min MS(ESIpos): m/z = 464 (M + H) A 238

546.47 46.5 LCMS: Rt =4.71 min MS(ESIpos): m/z = 448 (M + H) A 239

526.05 34.9 LCMS: Rt =4.58 min MS(ESIpos): m/z = 526 (M + H) A 240

501.62 88.1 LCMS: Rt =4.61 min MS(ESIpos): m/z = 502 (M + H) A 241

475.48 91 LCMS: Rt =4.37 min MS(ESIpos): m/z = 476 (M + H) A 242

555.59 73 LCMS: Rt =4.59 min MS(ESIpos): m/z = 556 (M + H) A 243

542.00 48 LCMS: Rt =4.60 min MS(ESIpos): m/z = 542 (M + H) A 244

560.45 27.1 LCMS: Rt =5.07 min MS(ESIpos): m/z = 560 (M + H) B 245

540.03 56 LCMS: Rt =2.95 min MS(ESIpos): m/z = 540 (M + H) B 246

547.66 43 LCMS: Rt =3.01 min MS(ESIpos): m/z = 548 (M + H) B 247

546.42 16.05 LCMS: Rt =4.66 min MS(ESIpos): m/z = 546 (M + H) A 248

459.54 65.2 LCMS: Rt =4.00 min MS(ESIpos): m/z = 460 (M + H) A 249

467.52 62 LCMS: Rt =4.00 min MS(ESIpos): m/z = 468 (M + H) A 250

515.65 85 LCMS: Rt =4.70 min MS(ESIpos): m/z = 416 (M + H) A 251

495.57 82 LCMS: Rt =4.50 min MS(ESIpos): m/z = 496 (M + H) A 252

523.63 54.4 LCMS: Rt =4.60 min MS(ESIpos): m/z = 524 (M + H) A 253

536.41 47.3 LCMS: Rt =4.74 min MS(ESIpos): m/z = 537 (M + H) A 254

537.94 20.5 LCMS: Rt =4.71 min MS(ESIpos): m/z = 538 (M + H) A 255

554.40 41.3 LCMS: Rt =4.90 min MS(ESIpos): m/z = 554 (M + H) A 256

554.40 60.5 LCMS: Rt =4.70 min MS(ESIpos): m/z = 554 (M + H) A 257

552.86 91.9 LCMS: Rt =4.90 min MS(ESIpos): m/z = 554 (M + H) A 258

597.32 59.9 LCMS: Rt =5.0 min MS(ESIpos): m/z = 598 (M + H) A 259

550.44 53 LCMS: Rt =4.75 min MS(ESIpos): m/z = 550 (M + H) A 260

536.41 60.34 LCMS: Rt =4.80 min MS(ESIpos): m/z = 538 (M + H) A 261

550.44 41.5 LCMS: Rt =4.80 min MS(ESIpos): m/z = 550 (M + H) A 262

533.98 45.4 LCMS: Rt =4.60 min MS(ESIpos): m/z = 534 (M + H) A 263

537.94 28 LCMS: Rt =4.70 min MS(ESIpos): m/z = 538 (M + H) A 264

537.94 50.6 LCMS: Rt =4.54 min MS(ESIpos): m/z = 538,2 (M + H) A 265

552.98 26 LCMS: Rt =4.60 min MS(ESIpos): m/z = 538 (M + H) A 266

515.99 53 LCMS: Rt =5.34 min MS(ESIpos): m/z = 538 (M + H) A 267

536.41 15 LCMS: Rt =4.28 min MS(ESIpos): m/z = 536 (M + H) A 268

495.57 56.1 LCMS: Rt =5.04 min MS(ESIpos): m/z = 496 (M + H) A 269

515.99 79.8 LCMS: Rt =2.75 min MS(ESIpos): m/z = 516 (M + H) B 270

533.98 76 LCMS: Rt =2.76 min MS(ESIpos): m/z = 534 (M + H) B 271

530.02 74.4 LCMS: Rt =2.89 min MS(ESIpos): m/z = 530 (M + H) B 272

516.98 73 LCMS: Rt =2.19 min MS(ESIpos): m/z = 517 (M + H) B 273

550.44 73.1 LCMS: Rt =2.92 min MS(ESIpos): m/z = 550 (M + H) B 274

515.99 100 LCMS: Rt =2.76 min MS(ESIpos): m/z = 516 (M + H) B 275

533.98 77.3 LCMS: Rt =2.78 min MS(ESIpos): m/z = 534 (M + H) B 276

530.02 78.3 LCMS: Rt =2.90 min MS(ESIpos): m/z = 530 (M + H) B 277

530.02 72.1 LCMS: Rt =2.78 min MS(ESIpos): m/z = 530 (M + H) B 278

516.98 67 LCMS: Rt =2.00 min MS(ESIpos): m/z = 517 (M + H) B 279

516.98 71 LCMS: Rt =1.95 min MS(ESIpos): m/z = 517 (M + H) B 280

550.44 77.2 LCMS: Rt =2.76 min MS(ESIpos): m/z = 550 (M + H) B 281

550.44 69.4 LCMS: Rt =2.79 min MS(ESIpos): m/z = 550 (M + H) B 282

550.44 71.5 LCMS: Rt =4.58 min MS(ESIpos): m/z = 550 (M + H) A 283

551.97 73.1 LCMS: Rt =4.46 min MS(ESIpos): m/z = 551 (M + H) A 284

568.43 64.2 LCMS: Rt =4.63 min MS(ESIpos): m/z = 568 (M + H) A 285

584.88 80.04 LCMS: Rt =4.84 min MS(ESIpos): m/z = 586 (M + H) A 286

599.99 73.16 LCMS: Rt =4.76 min MS(ESIpos): m/z = 600 (M + H) A 287

566.89 70.81 LCMS: Rt =4.74 min MS(ESIpos): m/z = 566 (M + H) A 288

533.43 44.12 LCMS: Rt =3.26 min MS(ESIpos): m/z = 533 (M + H) A 289

498.00 93.8 MS(ESIpos): m/z = 498 (M + H) HPLC: Rt =4.74 min C 290

566.00 94 MS(ESIpos): m/z = 566 (M + H) HPLC: Rt =4.98 min C 291

566.00 96 MS(ESIpos): m/z = 566 (M + H) HPLC: Rt =4.97 min C 292

566.00 95 MS(ESIpos): m/z = 566 (M + H) HPLC: Rt =4.98 min C 293

526.05 94 MS(ESIpos): m/z = 526 (M + H) HPLC: Rt =4.97 min C 294

530.02 95 MS(ESIpos): m/z = 530 (M + H) HPLC: Rt =4.85 min C 295

533.98 94 MS(ESIpos): m/z = 534 (M + H) HPLC: Rt =4.77 min C 296

566.89 93 MS(ESIpos): m/z = 566 (M + H) HPLC: Rt =5.12 min C 297

542.01 90 MS(ESIpos): m/z = 542 (M + H) HPLC: Rt =4.64 min C 298

504.03 91 MS(ESIpos): m/z = 504 (M + H) HPLC: Rt =4.66 min C 299

554.09 93 MS(ESIpos): m/z = 554 (M + H) HPLC: Rt =4.95 min C 300

498.99 95 MS(ESIpos): m/z = 499 (M + H) HPLC: Rt =4.09 min C 301

498.99 92 MS(ESIpos): m/z = 499 (M + H) HPLC: Rt =4.03 min C 302

498.99 93 MS(ESIpos): m/z = 499 (M + H) HPLC: Rt =4.09 min C 303

513.02 94 MS(ESIpos): m/z = 513 (M + H) HPLC: Rt =4.01 min C 304

513.02 89 MS(ESIpos): m/z = 513 (M + H) HPLC: Rt =4.05 min C 305

513.02 87 MS(ESIpos): m/z = 513 (M + H) HPLC: Rt =4.04 min C 306

533.43 92 MS(ESIpos): m/z = 533 (M + H) HPLC: Rt =4.52 min C 307

560.03 94 MS(ESIpos): m/z = 560 (M + H) HPLC: Rt =4.58 min C 308

501.99 94 MS(ESIpos): m/z = 502 (M + H) HPLC: Rt =4.68 min C 309

517.01 97 MS(ESIpos): m/z = 517 (M + H) HPLC: Rt =4.07 min C 310

558.10 48 MS(ESIpos): m/z = 558 (M + H) HPLC: Rt =4.23 min C

1. A compound of the formula (I) or (Ia),

in which A is (C₁-C₆)-alkanediyl, E is a bond or (C₁-C₆)-alkanediyl, Y is CO or SO₂, R¹, R², R³ and R⁴ are identical or different and are hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, carbamoyl or carboxyl, R⁵ is (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryl and heteroaryl are optionally substituted identically or differently by radicals selected from the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkylthio, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, carbamoyl, carboxyl, phenyl, 5- to 6-membered heteroaryl, propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxapropane-1,3-diyl or 1,4-dioxabutane-1,4-diyl, in which phenoxy, phenyl and 5- to 6-membered heteroaryl are optionally substituted identically or differently by trifluoromethyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or halogen, R⁶ and R⁷ are identical or different and are hydrogen, (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl, 4- to 12-heterocyclyl, or are (C₁-C₁₀)-alkyl which is optionally substituted by halogen or a radical selected from the group of (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl and 4- to 12-membered heterocyclyl, where aryl, heteroaryl, heterocyclyl and carbocyclyl are optionally substituted identically or differently by radicals selected from the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, 5- to 7-membered heterocyclyl, (C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkylthio, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, carbamoyl, carboxyl, phenyl, 5- to 6-membered heteroaryl, propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxapropane-1,3-diyl or 1,4-dioxabutane-1,4-diyl, or R⁶ and R⁷ together with the nitrogen atom form a 4- to 12-membered heterocyclyl radical which is bonded via nitrogen and which is optionally substituted identically or differently by radicals selected from the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyloxy, (C₁-C₆)-acyl, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, carbamoyl, carboxyl, (C₃-C₈)-Cycloalkyl and phenyl, where alkyl, cycloalkyl and phenyl are optionally substituted identically or differently by radicals selected from the group of halogen, phenyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and (C₁-C₆)-alkylthio, in which phenyl in turn is optionally substituted identically or differently by radicals selected from the group of halogen or methyl, R⁸ is hydrogen or (C₁-C₃)-alkyl which is optionally substituted by fluorine, R⁹ is hydrogen or (C₁-C₆)-alkyl, and the salts, hydrates and/or solvates thereof, with the exception of 2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.
 2. The compound as claimed in claim 1, where A is (C₁-C₆)-alkanediyl, E is a bond or (C₁-C₆)-alkanediyl, Y is CO, R¹, R², R³ and R⁴ are identical or different and are hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, carbamoyl or carboxyl, R⁵ is (C₆-C₁₀)-aryl or 5- to 10-membered heteroaryl, where aryl and heteroaryl are optionally substituted identically or differently by radicals selected from the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkylthio, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, carbamoyl, carboxyl, phenyl, 5- to 6-membered heteroaryl, propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxapropane-1,3-diyl or 1,4-dioxabutane-1,4-diyl, in which phenoxy, phenyl and 5- to 6-membered heteroaryl are in turn optionally substituted identically or differently by trifluoromethyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or halogen, R⁶ and R⁷ are identical or different and are hydrogen, (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, or are (C₁-C₁₀)-alkyl which is optionally substituted by halogen or a radical selected from the group of (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl and 4- to 12-membered heterocyclyl, where aryl, heteroaryl, heterocyclyl and carbocyclyl are optionally substituted identically or differently by radicals selected from the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, 5- to 7-membered heterocyclyl, (C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkylthio, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, carbamoyl, carboxyl, phenyl, 5- to 6-membered heteroaryl, propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxapropane-1,3-diyl or 1,4-dioxabutane-1,4-diyl, or R⁶ and R⁷ together with the nitrogen atom form a 4- to 12-membered heterocyclyl radical which is bonded via nitrogen and which is optionally substituted identically or differently by radicals selected from the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyloxy, (C₁-C₆)-acyl, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, carbamoyl, carboxyl, (C₃-C₈)-cycloalkyl and phenyl, where alkyl, cycloalkyl and phenyl in turn are optionally substituted identically or differently by one to three radicals selected from the group of halogen, phenyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and (C₁-C₆)-alkylthio, in which phenyl in turn is optionally substituted identically or differently by radicals selected from the group of halogen or methyl, R⁸ is hydrogen, R⁹ is hydrogen, and the salts, hydrates and/or solvates thereof, with the exception of 2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2-quinoxalinyl]-N-phenylacetamide.
 3. The compound as claimed in claim 1, where A is methylene, E is a bond, Y is CO, R¹, R², R³ and R⁴are identical or different and are hydrogen or halogen, R⁵ is phenyl which is optionally substituted identically or differently by one to three radicals selected from the group of methyl, isopropyl, halogen, trifluoromethyl and trifluoromethoxy, R⁶ and R⁷ are identical or different and are hydrogen, (C₁-C₆)-alkyl, phenyl or 5- to 8-membered carbocyclyl, where R⁶ and R⁷ are not both hydrogen, and where carbocyclyl and phenyl is optionally substituted identically or differently by radicals selected from the group of halogen, trifluoromethyl, trifluoromethoxy, methyl and methoxy, R⁸ is hydrogen, R⁹ is hydrogen, and the salts, hydrates and/or solvates thereof, with the exception of 2-[3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydro-2quinoxalinyl]-N-phenylacetamide.
 4. A process for preparing compounds of the formula (I) as claimed in claim 1, wherein [A] compounds of the general formula (II) or (IIa),

in which A, E, Y, R¹, R², R³, R⁴, R⁵, R⁸ and R⁹ have the meaning indicated in claim 1, and X¹ is halogen or hydroxyl, are reacted with compounds of the general formula (III)

in which R⁶ and R⁷ have the meaning indicated in claim 1, or the salts thereof, in inert solvents, where appropriate in the presence of a base and where appropriate in the presence of condensing agents, or [C] compounds of the general formula (V),

in which A, Y, R¹, R², R³, R⁴, R⁶, R⁷ and R⁸ have the meaning indicated in claim 1, are reacted with compounds of the general formula (VI)

in which E and R⁵ have the meaning indicated in claim 1, and X³ is halogen, in inert solvents, where appropriate in the presence of a base.
 5. A compound of the formula (V)

in which A is (C₁-C₆)-alkanediyl, Y is CO or SO₂, R¹, R², R³ and R⁴ are identical or different and are hvdrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆-alkylaminocarbonyl, carbamoyl or carboxyl, R⁶ and R⁷ are identical or different and are hydrogen, (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl, 4- to 12- heterocyclyl, or are (C₁-C₁₀)-alkyl which is optionally substituted by halogen or a radical selected from the group of (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl and 4- to 12-membered heterocyclyl, where aryl, heteroaryl, heterocyclyl and carbocyclyl are optionally substituted identically or differently by radicals selected from the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, 5- to 7-membered heterocyclyl, (C₁-C₆)-alkoxy, phenoxy, (C₁-C₆)-alkylthio, mono- or di-(C₁-C₆)-alkylamino, (C₁-₆)-acyl, (C₁-C₆)-acyloxy, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆-alkylaminocarbonyl, carbamoyl, carboxyl, phenyl, 5- to 6-membered heteroaryl, propane-1,3-diyl, butane-1,4-diyl, 1,3-dioxapropane-1,3-diyl or 1,4-dioxabutane-1,4-diyl, or R⁶ and R⁷ together with the nitrogen atom form a 4- to 12-membered heterocyclyl radical which is bonded via nitrogen and which is optionally substituted identically or differently by radicals selected from the group of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, mono- or di-(C₁-C₆)-alkylamino, (C₁-C₆)-acyloxy, (C₁-C₆)-acyl, (C₁-C₆)-acylamino, (C₁-C₆)-alkoxycarbonyl, mono- or di-(C₁-C₆)-alkylaminocarbonyl, carbamoyl, carboxyl, (C₃-C₈)-cycloalkyl and phenyl, where alkyl, cycloalkyl and phenyl are optionally substituted identically or differently by radicals selected from the group of halogen, phenyl, (C₁-₆)-alkyl, (C₁-C₆)-alkoxy and (C₁-C₆)-alkylthio, in which phenyl in turn is optionally substituted identically or differently by radicals selected from the group of halogen or methyl, R⁸ is hydrogen or (C₁-C₃)-alkyl which is optionally substituted by fluorine, and the salts, hydrates and/or solvates thereof.
 6. (Cancelled).
 7. A pharmaceutical composition comprising one or more of the compounds as claimed in claim 1 mixed together with one or more pharmaceutically suitable, essentially nontoxic carrier or excipient.
 8. A method for the treatment and/or prophylaxis of states of pain comprising administering to a subject in need thereof an effective amount of one or more compounds of claim
 1. 9. (Cancelled). 